Modulation of fetoprotein transcription factor expression

ABSTRACT

Compounds, compositions and methods are provided for modulating the expression of fetoprotein transcription factor. The compositions comprise oligonucleotides, targeted to nucleic acid encoding fetoprotein transcription factor. Methods of using these compounds for modulation of fetoprotein transcription factor expression and for diagnosis and treatment of disease associated with expression of fetoprotein transcription factor are provided.

FIELD OF THE INVENTION

[0001] The present invention provides compositions and methods for modulating the expression of fetoprotein transcription factor. In particular, this invention relates to compounds, particularly oligonucleotide compounds, which, in preferred embodiments, hybridize with nucleic acid molecules encoding fetoprotein transcription factor. Such compounds are shown herein to modulate the expression of fetoprotein transcription factor.

BACKGROUND OF THE INVENTION

[0002] In eukaryotes, control of metabolism is affected, in part, by regulation of gene expression. Two key regulatory pathways are affected by oxysterols; one involves a sterol-dependent feedback mechanism and is controlled by the sterol response element binding protein (SREBP), and the second involves the modulation by a feedforward mechanism of cholesterol utilization for either bile acid or steroid hormone synthesis by nuclear receptors. Nuclear hormone receptors are ligand-regulated transcription factors that mediate the transcriptional activity of small lipophilic signaling molecules such as steroids, retinoids and thyroid hormones. The conversion of cholesterol to bile acids produces the detergent necessary for the digestion and absorption of lipid nutrients as well as providing a metabolic pathway through which excessive cholesterol can be removed from the body. The rate-limiting step in bile acid biosynthesis is catalyzed by the enzyme, cholesterol 7-alpha-hydroxylase (CYP7A1), and the expression of the gene encoding the CYP7A1 enzyme is coordinately regulated by nuclear receptors. Bile acid activation of the farnesoid X receptor (FXR) represses the expression of CYP7A1 by increasing the expression of small heterodimer partner (SHP), a non-DNA-binding protein which associates with and inhibits the activity of the fetoprotein transcription factor (also known as FTF, hFTF, liver receptor homologue 1, LRH-1, Orphan nuclear receptor NR5A2, pancreas homologue receptor 1, PHR-1, hepatocytic transcription factor, b1-binding factor, hB1F, B1F2, CYP7A promoter-binding factor, CPF, fetoprotein-alpha 1 (AFP) transcription factor, FTZ-F1 related protein and FTZ-F1beta), a promotor-specific activator of the CYP7A1 gene. The fetoprotein transcription factor is activated by cholesterol derivatives and is believed to negatively regulate cholesterol metabolism, maintain adult liver homeostatic processes and prevent cholesterol affluence by promoting bile production, as well as playing a role in developmental gene expression (Davis et al., J. Lipid Res., 2002, 43, 533-543; Goodwin et al., Mol. Cell, 2000, 6, 517-526; Lu et al., Mol. Cell, 2000, 6, 507-515; Schoonjans et al., Biochim. Biophys. Acta, 2000, 1529, 114-125).

[0003] The human fetoprotein transcription factor gene was originally identified in a degenerate PCR screen for human cDNAs encoding proteins bearing zinc finger motifs similar to those found in members of the nuclear receptor superfamily (Becker-Andre et al., Biochem. Biophys. Res. Commun., 1993, 194, 1371-1379). A cDNA representing the fetoprotein transcription factor gene transcript was subsequently reported as a novel hepatocyte transcription factor found to bind to the B1 region of enhancer II of hepatitis B virus (HBV), an essential cis-element for transcriptional regulation of HBV gene expression (Li et al., J. Biol. Chem., 1998, 273, 29022-29031). The human fetoprotein transcription factor gene is expressed in the yolk sac, intestine, pancreas and liver, and has been mapped to human chromosomal region 1q31-32.1, a locus exhibiting frequent rearrangements in human tumors such as hepatomas (Galarneau et al., Cytogenet. Cell Genet., 1998, 82, 269-270; Li et al., J. Biol. Chem., 1998, 273, 29022-29031). Additionally, fetoprotein transcription factor mRNA transcripts are expressed at high levels in human steroidogenic tissues, particularly ovary and testis, suggesting that fetoprotein transcription factor plays an important role in regulation of gonadal function (Sirianni et al., J. Endocrinol., 2002, 174, R13-17).

[0004] Several splice variants of the fetoprotein transcription factor gene have been identified: exon mapping has delimited several 5′- and 3′-splice variants of the mouse fetoprotein transcription factor gene (Pare et al., J. Biol. Chem., 2001, 276, 13136-13144), two isoforms of the rat fetoprotein transcription factor gene product are known to exist (Galarneau et al., Mol. Cell. Biol., 1996, 16, 3853-3865; Nawata et al., J. Steroid Biochem. Mol. Biol., 1999, 69, 323-328), and a splicing isoform of the human fetoprotein transcription factor gene encoding an extra 46 amino acids has also been identified (Li et al., J. Biol. Chem., 1998, 273, 29022-29031).

[0005] In addition to regulating the liver-specific expression of 7-alpha-hydroxylase gene, fetoprotein transcription factor plays a crucial role in regulating the expression of sterol 12-alpha-hydroxylase, the specific enzyme required for cholic acid synthesis in bile acid biosynthetic pathways (del Castillo-Olivares and Gil, J. Biol. Chem., 2000, 275, 17793-17799; Yang et al., Biochim. Biophys. Acta, 2002, 1583, 63-73).

[0006] In a molecular mechanism similar to its bile salt-mediated repression of CYP7A1, fetoprotein transcription factor was also found to transactivate the human cholesterol ester transfer protein (CETP) gene promoter, potentiating the sterol-mediated induction of human CETP gene by liver X receptor (Luo et al., J. Biol. Chem., 2001, 276, 24767-24773).

[0007] Proper control of cholesterol homeostasis is crucial, and aberrant regulation of cholesterol homeostasis is associated with severe malformations in early development; furthermore, abnormal cholesterol metabolism can lead to many degenerative conditions such as atherosclerotic vascular disease, cholestasis, and gallstone disease (del Castillo-Olivares and Gil, J. Biol. Chem., 2000, 275, 17793-17799; Schoonjans et al., Biochim. Biophys. Acta, 2000, 1529, 114-125). Fetoprotein transcription factor is believed to also contribute to the development of human cancers. Fetoprotein transcription factor strongly activates promoter II of the CYP19 gene which encodes the aromatase protein that catalyzes estrogen biosynthesis from c₁₉ steroids in breast adipose tissue. Fetoprotein transcription factor appears to be a preadipocyte-specific nuclear receptor that regulates expression of aromatase in adipose and estrogenic tissues, and alterations in fetoprotein transcription factor expression and/or activity may have considerable effects on local estrogen production and breast cancer development (Clyne et al., J. Biol. Chem., 2002, 277, 20591-20597).

[0008] Viral hepatitis B is a leading cause of liver disease and primary hepatocellular carcinoma (HCC), and because the interaction of human fetoprotein transcription factor with enhancer II of HBV was found to be crucial for liver-specific transcription and DNA replication of the virus (Xie et al., J. Gen. Virol., 2001, 82, 531-535), fetoprotein transcription factor is also believed to be involved in liver carcinogenesis secondary to hepatitis B infection. Modulation of fetoprotein transcription factor function has been proposed to be a means for antagonizing HBV replication (Gilbert et al., J. Virol., 2000, 74, 5032-5039; Xie et al., J. Gen. Virol., 2001, 82, 531-535). Fetoprotein transcription factor regulation of HBV enhancer I has also been hypothesized to play a role in hepatocellular carcinogenesis (Shamay et al., Oncogene, 2001, 20, 6811-6819).

[0009] Disclosed and claimed in U.S. Pat. No. 5,958,697, 6,027,901 and 6,297,019 is a recombinant nucleic acid comprising a strand of sequence selected from a group of sequences wherein the human fetoprotein transcription factor gene is a member of said group, an isolated cell comprising said nucleic acid, a method of making a fetoprotein transcription factor polypeptide, a method of screening for an agent which modulates the interaction of a fetoprotein transcription factor polypeptide to a binding target, an isolated polypeptide, and a recombinant polynucleotide comprising a cDNA which comprises a coding region encoding at least ten contiguous amino acid residues of the fetoprotein transcription factor polypeptide (Shan and Nitta, 2000; Shan and Nitta, 1999; Shan and Nitta, 2001).

[0010] Currently, there are no known therapeutic agents which effectively inhibit the synthesis of fetoprotein transcription factor and to date, investigative strategies aimed at modulating fetoprotein transcription factor function have involved the use of a dominant negative mutant and an interfering peptide.

[0011] Expression of a carboxy-terminal truncated fetoprotein transcription factor mutant protein was found to act in a dominant negative fashion and strongly deactivate core promoter interactions with enhancer I of HBV, suggesting a means of interfering with HBV infection (Gilbert et al., J. Virol., 2000, 74, 5032-5039). An alpha-1-antitrypsin-derived carboxy-terminal serpin peptide called C-36 was found to act as a powerful and specific transcriptional downregulator of bile acid synthesis via inhibition of the CYP7A1 promoter. The C-36 peptide was reported to directly interact with fetoprotein transcription factor and prevent binding to its DNA recognition site, resulting in suppression of transcription of 7-alpha- and 12-alpha-hydroxylase transcription. (Gerbod-Giannone et al., J. Biol. Chem., 2002, 277, 42973-42980). However, these strategies are untested as therapeutic protocols.

[0012] Consequently, there remains a long felt need for additional agents capable of effectively inhibiting fetoprotein transcription factor function.

[0013] Antisense technology is emerging as an effective means for reducing the expression of specific gene products and may therefore prove to be uniquely useful in a number of therapeutic, diagnostic, and research applications for the modulation of fetoprotein transcription factor expression.

[0014] The present invention provides compositions and methods for modulating fetoprotein transcription factor expression.

SUMMARY OF THE INVENTION

[0015] The present invention is directed to compounds, especially nucleic acid and nucleic acid-like oligomers, which are targeted to a nucleic acid encoding fetoprotein transcription factor, and which modulate the expression of fetoprotein transcription factor. Pharmaceutical and other compositions comprising the compounds of the invention are also provided. Further provided are methods of screening for modulators of fetoprotein transcription factor and methods of modulating the expression of fetoprotein transcription factor in cells, tissues or animals comprising contacting said cells, tissues or animals with one or more of the compounds or compositions of the invention. Methods of treating an animal, particularly a human, suspected of having or being prone to a disease or condition associated with expression of fetoprotein transcription factor are also set forth herein. Such methods comprise administering a therapeutically or prophylactically effective amount of one or more of the compounds or compositions of the invention to the person in need of treatment.

DETAILED DESCRIPTION OF THE INVENTION

[0016] A. Overview of the Invention

[0017] The present invention employs compounds, preferably oligonucleotides and similar species for use in modulating the function or effect of nucleic acid molecules encoding fetoprotein transcription factor. This is accomplished by providing oligonucleotides which specifically hybridize with one or more nucleic acid molecules encoding fetoprotein transcription factor. As used herein, the terms “target nucleic acid” and “nucleic acid molecule encoding fetoprotein transcription factor” have been used for convenience to encompass DNA encoding fetoprotein transcription factor, RNA (including pre-mRNA and mRNA or portions thereof) transcribed from such DNA, and also cDNA derived from such RNA. The hybridization of a compound of this invention with its target nucleic acid is generally referred to as “antisense”. Consequently, the preferred mechanism believed to be included in the practice of some preferred embodiments of the invention is referred to herein as “antisense inhibition.” Such antisense inhibition is typically based upon hydrogen bonding-based hybridization of oligonucleotide strands or segments such that at least one strand or segment is cleaved, degraded, or otherwise rendered inoperable. In this regard, it is presently preferred to target specific nucleic acid molecules and their functions for such antisense inhibition.

[0018] The functions of DNA to be interfered with can include replication and transcription. Replication and transcription, for example, can be from an endogenous cellular template, a vector, a plasmid construct or otherwise. The functions of RNA to be interfered with can include functions such as translocation of the RNA to a site of protein translation, translocation of the RNA to sites within the cell which are distant from the site of RNA synthesis, translation of protein from the RNA, splicing of the RNA to yield one or more RNA species, and catalytic activity or complex formation involving the RNA which may be engaged in or facilitated by the RNA. One preferred result of such interference with target nucleic acid function is modulation of the expression of fetoprotein transcription factor. In the context of the present invention, “modulation” and “modulation of expression” mean either an increase (stimulation) or a decrease (inhibition) in the amount or levels of a nucleic acid molecule encoding the gene, e.g., DNA or RNA. Inhibition is often the preferred form of modulation of expression and mRNA is often a preferred target nucleic acid.

[0019] In the context of this invention, “hybridization” means the pairing of complementary strands of oligomeric compounds. In the present invention, the preferred mechanism of pairing involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleoside or nucleotide bases (nucleobases) of the strands of oligomeric compounds. For example, adenine and thymine are complementary nucleobases which pair through the formation of hydrogen bonds. Hybridization can occur under varying circumstances.

[0020] An antisense compound is specifically hybridizable when binding of the compound to the target nucleic acid interferes with the normal function of the target nucleic acid to cause a loss of activity, and there is a sufficient degree of complementarity to avoid non-specific binding of the antisense compound to non-target nucleic acid sequences under conditions in which specific binding is desired, i.e., under physiological conditions in the case of in vivo assays or therapeutic treatment, and under conditions in which assays are performed in the case of in vitro assays.

[0021] In the present invention the phrase “stringent hybridization conditions” or “stringent conditions” refers to conditions under which a compound of the invention will hybridize to its target sequence, but to a minimal number of other sequences. Stringent conditions are sequence-dependent and will be different in different circumstances and in the context of this invention, “stringent conditions” under which oligomeric compounds hybridize to a target sequence are determined by the nature and composition of the oligomeric compounds and the assays in which they are being investigated.

[0022] “Complementary,” as used herein, refers to the capacity for precise pairing between two nucleobases of an oligomeric compound. For example, if a nucleobase at a certain position of an oligonucleotide (an oligomeric compound), is capable of hydrogen bonding with a nucleobase at a certain position of a target nucleic acid, said target nucleic acid being a DNA, RNA, or oligonucleotide molecule, then the position of hydrogen bonding between the oligonucleotide and the target nucleic acid is considered to be a complementary position. The oligonucleotide and the further DNA, RNA, or oligonucleotide molecule are complementary to each other when a sufficient number of complementary positions in each molecule are occupied by nucleobases which can hydrogen bond with each other. Thus, “specifically hybridizable” and “complementary” are terms which are used to indicate a sufficient degree of precise pairing or complementarity over a sufficient number of nucleobases such that stable and specific binding occurs between the oligonucleotide and a target nucleic acid.

[0023] It is understood in the art that the sequence of an antisense compound need not be 100% complementary to that of its target nucleic acid to be specifically hybridizable. Moreover, an oligonucleotide may hybridize over one or more segments such that intervening or adjacent segments are not involved in the hybridization event (e.g., a loop structure or hairpin structure). It is preferred that the antisense compounds of the present invention comprise at least 70% sequence complementarity to a target region within the target nucleic acid, more preferably that they comprise 90% sequence complementarity and even more preferably comprise 95% sequence complementarity to the target region within the target nucleic acid sequence to which they are targeted. For example, an antisense compound in which 18 of 20 nucleobases of the antisense compound are complementary to a target region, and would therefore specifically hybridize, would represent 90 percent complementarity. In this example, the remaining noncomplementary nucleobases may be clustered or interspersed with complementary nucleobases and need not be contiguous to each other or to complementary nucleobases. As such, an antisense compound which is 18 nucleobases in length having 4 (four) noncomplementary nucleobases which are flanked by two regions of complete complementarity with the target nucleic acid would have 77.8% overall complementarity with the target nucleic acid and would thus fall within the scope of the present invention. Percent complementarity of an antisense compound with a region of a target nucleic acid can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs known in the art (Altschul et al., J. Mol. Biol., 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656).

[0024] B. Compounds of the Invention

[0025] According to the present invention, compounds include antisense oligomeric compounds, antisense oligonucleotides, ribozymes, external guide sequence (EGS) oligonucleotides, alternate splicers, primers, probes, and other oligomeric compounds which hybridize to at least a portion of the target nucleic acid. As such, these compounds may be introduced in the form of single-stranded, double-stranded, circular or hairpin oligomeric compounds and may contain structural elements such as internal or terminal bulges or loops. Once introduced to a system, the compounds of the invention may elicit the action of one or more enzymes or structural proteins to effect modification of the target nucleic acid. One non-limiting example of such an enzyme is RNAse H, a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. It is known in the art that single-stranded antisense compounds which are “DNA-like” elicit RNAse H. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide-mediated inhibition of gene expression. Similar roles have been postulated for other ribonucleases such as those in the RNase III and ribonuclease L family of enzymes.

[0026] While the preferred form of antisense compound is a single-stranded antisense oligonucleotide, in many species the introduction of double-stranded structures, such as double-stranded RNA (dsRNA) molecules, has been shown to induce potent and specific antisense-mediated reduction of the function of a gene or its associated gene products. This phenomenon occurs in both plants and animals and is believed to have an evolutionary connection to viral defense and transposon silencing.

[0027] The first evidence that dsRNA could lead to gene silencing in animals came in 1995 from work in the nematode, Caenorhabditis elegans (Guo and Kempheus, Cell, 1995, 81, 611-620). Montgomery et al. have shown that the primary interference effects of dsRNA are posttranscriptional (Montgomery et al., Proc. Natl. Acad. Sci. USA, 1998, 95, 15502-15507). The posttranscriptional antisense mechanism defined in Caenorhabditis elegans resulting from exposure to double-stranded RNA (dsRNA) has since been designated RNA interference (RNAi). This term has been generalized to mean antisense-mediated gene silencing involving the introduction of dsRNA leading to the sequence-specific reduction of endogenous targeted mRNA levels (Fire et al., Nature, 1998, 391, 806-811). Recently, it has been shown that it is, in fact, the single-stranded RNA oligomers of antisense polarity of the dsRNAs which are the potent inducers of RNAi (Tijsterman et al., Science, 2002, 295, 694-697).

[0028] In the context of this invention, the term “oligomeric compound” refers to a polymer or oligomer comprising a plurality of monomeric units. In the context of this invention, the term “oligonucleotide” refers to an oligomer or polymer of ribonucleic acid (RNA) or deoxyribonucleic acid (DNA) or mimetics, chimeras, analogs and homologs thereof. This term includes oligonucleotides composed of naturally occurring nucleobases, sugars and covalent internucleoside (backbone) linkages as well as oligonucleotides having non-naturally occurring portions which function similarly. Such modified or substituted oligonucleotides are often preferred over native forms because of desirable properties such as, for example, enhanced cellular uptake, enhanced affinity for a target nucleic acid and increased stability in the presence of nucleases.

[0029] While oligonucleotides are a preferred form of the compounds of this invention, the present invention comprehends other families of compounds as well, including but not limited to oligonucleotide analogs and mimetics such as those described herein.

[0030] The compounds in accordance with this invention preferably comprise from about 8 to about 80 nucleobases (i.e. from about 8 to about 80 linked nucleosides). One of ordinary skill in the art will appreciate that the invention embodies compounds of 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, or 80 nucleobases in length.

[0031] In one preferred embodiment, the compounds of the invention are 12 to 50 nucleobases in length. One having ordinary skill in the art will appreciate that this embodies compounds of 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 nucleobases in length.

[0032] In another preferred embodiment, the compounds of the invention are 15 to 30 nucleobases in length. One having ordinary skill in the art will appreciate that this embodies compounds of 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleobases in length.

[0033] Particularly preferred compounds are oligonucleotides from about 12 to about 50 nucleobases, even more preferably those comprising from about 15 to about 30 nucleobases.

[0034] Antisense compounds 8-80 nucleobases in length comprising a stretch of at least eight (8) consecutive nucleobases selected from within the illustrative antisense compounds are considered to be suitable antisense compounds as well.

[0035] Exemplary preferred antisense compounds include oligonucleotide sequences that comprise at least the 8 consecutive nucleobases from the 5′-terminus of one of the illustrative preferred antisense compounds (the remaining nucleobases being a consecutive stretch of the same oligonucleotide beginning immediately upstream of the 5′-terminus of the antisense compound which is specifically hybridizable to the target nucleic acid and continuing until the oligonucleotide contains about 8 to about 80 nucleobases). Similarly preferred antisense compounds are represented by oligonucleotide sequences that comprise at least the 8 consecutive nucleobases from the 3′-terminus of one of the illustrative preferred antisense compounds (the remaining nucleobases being a consecutive stretch of the same oligonucleotide beginning immediately downstream of the 3′-terminus of the antisense compound which is specifically hybridizable to the target nucleic acid and continuing until the oligonucleotide contains about 8 to about 80 nucleobases). One having skill in the art armed with the preferred antisense compounds illustrated herein will be able, without undue experimentation, to identify further preferred antisense compounds.

[0036] C. Targets of the Invention

[0037] “Targeting” an antisense compound to a particular nucleic acid molecule, in the context of this invention, can be a multistep process. The process usually begins with the identification of a target nucleic acid whose function is to be modulated. This target nucleic acid may be, for example, a cellular gene (or mRNA transcribed from the gene) whose expression is associated with a particular disorder or disease state, or a nucleic acid molecule from an infectious agent. In the present invention, the target nucleic acid encodes fetoprotein transcription factor.

[0038] The targeting process usually also includes determination of at least one target region, segment, or site within the target nucleic acid for the antisense interaction to occur such that the desired effect, e.g., modulation of expression, will result. Within the context of the present invention, the term “region” is defined as a portion of the target nucleic acid having at least one identifiable structure, function, or characteristic. Within regions of target nucleic acids are segments. “Segments” are defined as smaller or sub-portions of regions within a target nucleic acid “Sites,” as used in the present invention, are defined as positions within a target nucleic acid.

[0039] Since, as is known in the art, the translation initiation codon is typically 5′-AUG (in transcribed mRNA molecules; 5′-ATG in the corresponding DNA molecule), the translation initiation codon is also referred to as the “AUG codon,” the “start codon” or the “AUG start codon”. A minority of genes have a translation initiation codon having the RNA sequence 5′-GUG, 5′-UUG or 5′-CUG, and 5′-AUA, 5′-ACG and 5′-CUG have been shown to function in vivo. Thus, the terms “translation initiation codon” and “start codon” can encompass many codon sequences, even though the initiator amino acid in each instance is typically methionine (in eukaryotes) or formylmethionine (in prokaryotes). It is also known in the art that eukaryotic and prokaryotic genes may have two or more alternative start codons, any one of which may be preferentially utilized for translation initiation in a particular cell type or tissue, or under a particular set of conditions. In the context of the invention, “start codon” and “translation initiation codon” refer to the codon or codons that are used in vivo to initiate translation of an mRNA transcribed from a gene encoding fetoprotein transcription factor, regardless of the sequence(s) of such codons. It is also known in the art that a translation termination codon (or “stop codon”) of a gene may have one of three sequences, i.e., 5′-UAA, 5′-UAG and 5′-UGA (the corresponding DNA sequences are 5′-TAA, 5′-TAG and 5′-TGA, respectively).

[0040] The terms “start codon region” and “translation initiation codon region” refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5′ or 3′) from a translation initiation codon. Similarly, the terms “stop codon region” and “translation termination codon region” refer to a portion of such an mRNA or gene that encompasses from about 25 to about 50 contiguous nucleotides in either direction (i.e., 5′ or 3′) from a translation termination codon. Consequently, the “start codon region” (or “translation initiation codon region”) and the “stop codon region” (or “translation termination codon region”) are all regions which may be targeted effectively with the antisense compounds of the present invention.

[0041] The open reading frame (ORF) or “coding region,” which is known in the art to refer to the region between the translation initiation codon and the translation termination codon, is also a region which may be targeted effectively. Within the context of the present invention, a preferred region is the intragenic region encompassing the translation initiation or termination codon of the open reading frame (ORF) of a gene.

[0042] Other target regions include the 5′ untranslated region (5′ UTR), known in the art to refer to the portion of an mRNA in the 5′ direction from the translation initiation codon, and thus including nucleotides between the 5′ cap site and the translation initiation codon of an mRNA (or corresponding nucleotides on the gene), and the 3′ untranslated region (3′ UTR), known in the art to refer to the portion of an mRNA in the 3′ direction from the translation termination codon, and thus including nucleotides between the translation termination codon and 3′ end of an mRNA (or corresponding nucleotides on the gene). The 5′ cap site of an mRNA comprises an N7-methylated guanosine residue joined to the 5′-most residue of the mRNA via a 5′-5′ triphosphate linkage. The 5′ cap region of an MRNA is considered to include the 5′ cap structure itself as well as the first 50 nucleotides adjacent to the cap site. It is also preferred to target the 5′ cap region.

[0043] Although some eukaryotic mRNA transcripts are directly translated, many contain one or more regions, known as “introns,” which are excised from a transcript before it is translated. The remaining (and therefore translated) regions are known as “exons” and are spliced together to form a continuous mRNA sequence. Targeting splice sites, i.e., intron-exon junctions or exon-intron junctions, may also be particularly useful in situations where aberrant splicing is implicated in disease, or where an overproduction of a particular splice product is implicated in disease. Aberrant fusion junctions due to rearrangements or deletions are also preferred target sites. mRNA transcripts produced via the process of splicing of two (or more) mRNAs from different gene sources are known as “fusion transcripts”. It is also known that introns can be effectively targeted using antisense compounds targeted to, for example, DNA or pre-mRNA.

[0044] It is also known in the art that alternative RNA transcripts can be produced from the same genomic region of DNA. These alternative transcripts are generally known as “variants”. More specifically, “pre-mRNA variants” are transcripts produced from the same genomic DNA that differ from other transcripts produced from the same genomic DNA in either their start or stop position and contain both intronic and exonic sequence.

[0045] Upon excision of one or more exon or intron regions, or portions thereof during splicing, pre-mRNA variants produce smaller “mRNA variants”. Consequently, mRNA variants are processed pre-mRNA variants and each unique pre-mRNA variant must always produce a unique mRNA variant as a result of splicing. These mRNA variants are also known as “alternative splice variants”. If no splicing of the pre-mRNA variant occurs then the pre-mRNA variant is identical to the mRNA variant.

[0046] It is also known in the art that variants can be produced through the use of alternative signals to start or stop transcription and that pre-mRNAs and mRNAs can possess more that one start codon or stop codon. Variants that originate from a pre-mRNA or mRNA that use alternative start codons are known as “alternative start variants” of that pre-mRNA or mRNA. Those transcripts that use an alternative stop codon are known as “alternative stop variants” of that pre-mRNA or mRNA. One specific type of alternative stop variant is the “polyA variant” in which the multiple transcripts produced result from the alternative selection of one of the “polyA stop signals” by the transcription machinery, thereby producing transcripts that terminate at unique polyA sites. Within the context of the invention, the types of variants described herein are also preferred target nucleic acids.

[0047] The locations on the target nucleic acid to which the preferred antisense compounds hybridize are hereinbelow referred to as “preferred target segments.” As used herein the term “preferred target segment” is defined as at least an 8-nucleobase portion of a target region to which an active antisense compound is targeted. While not wishing to be bound by theory, it is presently believed that these target segments represent portions of the target nucleic acid which are accessible for hybridization.

[0048] While the specific sequences of certain preferred target segments are set forth herein, one of skill in the art will recognize that these serve to illustrate and describe particular embodiments within the scope of the present invention. Additional preferred target segments may be identified by one having ordinary skill.

[0049] Target segments 8-80 nucleobases in length comprising a stretch of at least eight (8) consecutive nucleobases selected from within the illustrative preferred target segments are considered to be suitable for targeting as well.

[0050] Target segments can include DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 5′-terminus of one of the illustrative preferred target segments (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately upstream of the 5′-terminus of the target segment and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). Similarly preferred target segments are represented by DNA or RNA sequences that comprise at least the 8 consecutive nucleobases from the 3′-terminus of one of the illustrative preferred target segments (the remaining nucleobases being a consecutive stretch of the same DNA or RNA beginning immediately downstream of the 3′-terminus of the target segment and continuing until the DNA or RNA contains about 8 to about 80 nucleobases). One having skill in the art armed with the preferred target segments illustrated herein will be able, without undue experimentation, to identify further preferred target segments.

[0051] Once one or more target regions, segments or sites have been identified, antisense compounds are chosen which are sufficiently complementary to the target, i.e., hybridize sufficiently well and with sufficient specificity, to give the desired effect.

[0052] D. Screening and Target Validation

[0053] In a further embodiment, the “preferred target segments” identified herein may be employed in a screen for additional compounds that modulate the expression of fetoprotein transcription factor. “Modulators” are those compounds that decrease or increase the expression of a nucleic acid molecule encoding fetoprotein transcription factor and which comprise at least an 8-nucleobase portion which is complementary to a preferred target segment. The screening method comprises the steps of contacting a preferred target segment of a nucleic acid molecule encoding fetoprotein transcription factor with one or more candidate modulators, and selecting for one or more candidate modulators which decrease or increase the expression of a nucleic acid molecule encoding fetoprotein transcription factor. Once it is shown that the candidate modulator or modulators are capable of modulating (e.g. either decreasing or increasing) the expression of a nucleic acid molecule encoding fetoprotein transcription factor, the modulator may then be employed in further investigative studies of the function of fetoprotein transcription factor, or for use as a research, diagnostic, or therapeutic agent in accordance with the present invention.

[0054] The preferred target segments of the present invention may be also be combined with their respective complementary antisense compounds of the present invention to form stabilized double-stranded (duplexed) oligonucleotides.

[0055] Such double stranded oligonucleotide moieties have been shown in the art to modulate target expression and regulate translation as well as RNA processsing via an antisense mechanism. Moreover, the double-stranded moieties may be subject to chemical modifications (Fire et al., Nature, 1998, 391, 806-811; Timmons and Fire, Nature 1998, 395, 854; Timmons et al., Gene, 2001, 263, 103-112; Tabara et al., Science, 1998, 282, 430-431; Montgomery et al., Proc. Natl. Acad. Sci. USA, 1998, 95, 15502-15507; Tuschl et al., Genes Dev., 1999, 13, 3191-3197; Elbashir et al., Nature, 2001, 411, 494-498; Elbashir et al., Genes Dev. 2001, 15, 188-200). For example, such double-stranded moieties have been shown to inhibit the target by the classical hybridization of antisense strand of the duplex to the target, thereby triggering enzymatic degradation of the target (Tijsterman et al., Science, 2002, 295, 694-697).

[0056] The compounds of the present invention can also be applied in the areas of drug discovery and target validation. The present invention comprehends the use of the compounds and preferred target segments identified herein in drug discovery efforts to elucidate relationships that exist between fetoprotein transcription factor and a disease state, phenotype, or condition. These methods include detecting or modulating fetoprotein transcription factor comprising contacting a sample, tissue, cell, or organism with the compounds of the present invention, measuring the nucleic acid or protein level of fetoprotein transcription factor and/or a related phenotypic or chemical endpoint at some time after treatment, and optionally comparing the measured value to a non-treated sample or sample treated with a further compound of the invention. These methods can also be performed in parallel or in combination with other experiments to determine the function of unknown genes for the process of target validation or to determine the validity of a particular gene product as a target for treatment or prevention of a particular disease, condition, or phenotype.

[0057] E. Kits, Research Reagents, Diagnostics, and Therapeutics

[0058] The compounds of the present invention can be utilized for diagnostics, therapeutics, prophylaxis and as research reagents and kits. Furthermore, antisense oligonucleotides, which are able to inhibit gene expression with exquisite specificity, are often used by those of ordinary skill to elucidate the function of particular genes or to distinguish between functions of various members of a biological pathway.

[0059] For use in kits and diagnostics, the compounds of the present invention, either alone or in combination with other compounds or therapeutics, can be used as tools in differential and/or combinatorial analyses to elucidate expression patterns of a portion or the entire complement of genes expressed within cells and tissues.

[0060] As one nonlimiting example, expression patterns within cells or tissues treated with one or more antisense compounds are compared to control cells or tissues not treated with antisense compounds and the patterns produced are analyzed for differential levels of gene expression as they pertain, for example, to disease association, signaling pathway, cellular localization, expression level, size, structure or function of the genes examined. These analyses can be performed on stimulated or unstimulated cells and in the presence or absence of other compounds which affect expression patterns.

[0061] Examples of methods of gene expression analysis known in the art include DNA arrays or microarrays (Brazma and Vilo, FEBS Lett., 2000, 480, 17-24; Celis, et al., FEBS Lett., 2000, 480, 2-16), SAGE (serial analysis of gene expression) (Madden, et al., Drug Discov. Today, 2000, 5, 415-425), READS (restriction enzyme amplification of digested cDNAs) (Prashar and Weissman, Methods Enzymol., 1999, 303, 258-72), TOGA (total gene expression analysis) (Sutcliffe, et al., Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 1976-81), protein arrays and proteomics (Celis, et al., FEBS Lett., 2000, 480, 2-16; Jungblut, et al., Electrophoresis, 1999, 20, 2100-10), expressed sequence tag (EST) sequencing (Celis, et al., FEBS Lett., 2000, 480, 2-16; Larsson, et al., J. Biotechnol., 2000, 80, 143-57), subtractive RNA fingerprinting (SuRF) (Fuchs, et al., Anal. Biochem., 2000, 286, 91-98; Larson, et al., Cytometry, 2000, 41, 203-208), subtractive cloning, differential display (DD) (Jurecic and Belmont, Curr. Opin. Microbiol., 2000, 3, 316-21), comparative genomic hybridization (Carulli, et al., J. Cell Biochem. Suppl., 1998, 31, 286-96), FISH (fluorescent in situ hybridization) techniques (Going and Gusterson, Eur. J. Cancer, 1999, 35, 1895-904) and mass spectrometry methods (To, Comb. Chem. High Throughput Screen, 2000, 3, 235-41).

[0062] The compounds of the invention are useful for research and diagnostics, because these compounds hybridize to nucleic acids encoding fetoprotein transcription factor. For example, oligonucleotides that are shown to hybridize with such efficiency and under such conditions as disclosed herein as to be effective fetoprotein transcription factor inhibitors will also be effective primers or probes under conditions favoring gene amplification or detection, respectively. These primers and probes are useful in methods requiring the specific detection of nucleic acid molecules encoding fetoprotein transcription factor and in the amplification of said nucleic acid molecules for detection or for use in further studies of fetoprotein transcription factor. Hybridization of the antisense oligonucleotides, particularly the primers and probes, of the invention with a nucleic acid encoding fetoprotein transcription factor can be detected by means known in the art. Such means may include conjugation of an enzyme to the oligonucleotide, radiolabelling of the oligonucleotide or any other suitable detection means. Kits using such detection means for detecting the level of fetoprotein transcription factor in a sample may also be prepared.

[0063] The specificity and sensitivity of antisense is also harnessed by those of skill in the art for therapeutic uses. Antisense compounds have been employed as therapeutic moieties in the treatment of disease states in animals, including humans. Antisense oligonucleotide drugs, including ribozymes, have been safely and effectively administered to humans and numerous clinical trials are presently underway. It is thus established that antisense compounds can be useful therapeutic modalities that can be configured to be useful in treatment regimes for the treatment of cells, tissues and animals, especially humans.

[0064] For therapeutics, an animal, preferably a human, suspected of having a disease or disorder which can be treated by modulating the expression of fetoprotein transcription factor is treated by administering antisense compounds in accordance with this invention. For example, in one non-limiting embodiment, the methods comprise the step of administering to the animal in need of treatment, a therapeutically effective amount of a fetoprotein transcription factor inhibitor. The fetoprotein transcription factor inhibitors of the present invention effectively inhibit the activity of the fetoprotein transcription factor protein or inhibit the expression of the fetoprotein transcription factor protein. In one embodiment, the activity or expression of fetoprotein transcription factor in an animal is inhibited by about 10%. Preferably, the activity or expression of fetoprotein transcription factor in an animal is inhibited by about 30%. More preferably, the activity or expression of fetoprotein transcription factor in an animal is inhibited by 50% or more.

[0065] For example, the reduction of the expression of fetoprotein transcription factor may be measured in serum, adipose tissue, liver or any other body fluid, tissue or organ of the animal. Preferably, the cells contained within said fluids, tissues or organs being analyzed contain a nucleic acid molecule encoding fetoprotein transcription factor protein and/or the fetoprotein transcription factor protein itself.

[0066] The compounds of the invention can be utilized in pharmaceutical compositions by adding an effective amount of a compound to a suitable pharmaceutically acceptable diluent or carrier. Use of the compounds and methods of the invention may also be useful prophylactically.

[0067] F. Modifications

[0068] As is known in the art, a nucleoside is a base-sugar combination. The base portion of the nucleoside is normally a heterocyclic base. The two most common classes of such heterocyclic bases are the purines and the pyrimidines. Nucleotides are nucleosides that further include a phosphate group covalently linked to the sugar portion of the nucleoside. For those nucleosides that include a pentofuranosyl sugar, the phosphate group can be linked to either the 2′, 3′ or 5′ hydroxyl moiety of the sugar. In forming oligonucleotides, the phosphate groups covalently link adjacent nucleosides to one another to form a linear polymeric compound. In turn, the respective ends of this linear polymeric compound can be further joined to form a circular compound, however, linear compounds are generally preferred. In addition, linear compounds may have internal nucleobase complementarity and may therefore fold in a manner as to produce a fully or partially double-stranded compound. Within oligonucleotides, the phosphate groups are commonly referred to as forming the internucleoside backbone of the oligonucleotide. The normal linkage or backbone of RNA and DNA is a 3′ to 5′ phosphodiester linkage.

[0069] Modified Internucleoside Linkages (Backbones)

[0070] Specific examples of preferred antisense compounds useful in this invention include oligonucleotides containing modified backbones or non-natural internucleoside linkages. As defined in this specification, oligonucleotides having modified backbones include those that retain a phosphorus atom in the backbone and those that do not have a phosphorus atom in the backbone. For the purposes of this specification, and as sometimes referenced in the art, modified oligonucleotides that do not have a phosphorus atom in their internucleoside backbone can also be considered to be oligonucleosides.

[0071] Preferred modified oligonucleotide backbones containing a phosphorus atom therein include, for example, phosphorothioates, chiral phosphorothioates, phosphoro-dithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3′-alkylene phosphonates, 5′-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3′-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, selenophosphates and borano-phosphates having normal 3′-5′ linkages, 2′-5′ linked analogs of these, and those having inverted polarity wherein one or more internucleotide linkages is a 3′ to 3′, 5′ to 5′ or 2′ to 2′ linkage. Preferred oligonucleotides having inverted polarity comprise a single 3′ to 3′ linkage at the 3′-most internucleotide linkage i.e. a single inverted nucleoside residue which may be abasic (the nucleobase is missing or has a hydroxyl group in place thereof). Various salts, mixed salts and free acid forms are also included.

[0072] Representative United States patents that teach the preparation of the above phosphorus-containing linkages include, but are not limited to, U.S. Pat. Nos.: 3,687,808; 4,469,863; 4,476,301; 5,023,243; 5,177,196; 5,188,897; 5,264,423; 5,276,019; 5,278,302; 5,286,717; 5,321,131; 5,399,676; 5,405,939; 5,453,496; 5,455,233; 5,466,677; 5,476,925; 5,519,126; 5,536,821; 5,541,306; 5,550,111; 5,563,253; 5,571,799; 5,587,361; 5,194,599; 5,565,555; 5,527,899; 5,721,218; 5,672,697 and 5,625,050, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.

[0073] Preferred modified oligonucleotide backbones that do not include a phosphorus atom therein have backbones that are formed by short chain alkyl or cycloalkyl internucleoside linkages, mixed heteroatom and alkyl or cycloalkyl internucleoside linkages, or one or more short chain heteroatomic or heterocyclic internucleoside linkages. These include those having morpholino linkages (formed in part from the sugar portion of a nucleoside); siloxane backbones; sulfide, sulfoxide and sulfone backbones; formacetyl and thioformacetyl backbones; methylene formacetyl and thioformacetyl backbones; riboacetyl backbones; alkene containing backbones; sulfamate backbones; methyleneimino and methylenehydrazino backbones; sulfonate and sulfonamide backbones; amide backbones; and others having mixed N, O, S and CH₂ component parts.

[0074] Representative United States patents that teach the preparation of the above oligonucleosides include, but are not limited to, U.S. Pat. Nos.: 5,034,506; 5,166,315; 5,185,444; 5,214,134; 5,216,141; 5,235,033; 5,264,562; 5,264,564; 5,405,938; 5,434,257; 5,466,677; 5,470,967; 5,489,677; 5,541,307; 5,561,225; 5,596,086; 5,602,240; 5,610,289; 5,602,240; 5,608,046; 5,610,289; 5,618,704; 5,623,070; 5,663,312; 5,633,360; 5,677,437; 5,792,608; 5,646,269 and 5,677,439, certain of which are commonly owned with this application, and each of which is herein incorporated by reference.

[0075] Modified Sugar and Internucleoside Linkages-Mimetics

[0076] In other preferred oligonucleotide mimetics, both the sugar and the internucleoside linkage (i.e. the backbone), of the nucleotide units are replaced with novel groups. The nucleobase units are maintained for hybridization with an appropriate target nucleic acid. One such compound, an oligonucleotide mimetic that has been shown to have excellent hybridization properties, is referred to as a peptide nucleic acid (PNA). In PNA compounds, the sugar-backbone of an oligonucleotide is replaced with an amide containing backbone, in particular an aminoethylglycine backbone. The nucleobases are retained and are bound directly or indirectly to aza nitrogen atoms of the amide portion of the backbone. Representative United States patents that teach the preparation of PNA compounds include, but are not limited to, U.S.Pat. Nos.: 5,539,082; 5,714,331; and 5,719,262, each of which is herein incorporated by reference. Further teaching of PNA compounds can be found in Nielsen et al., Science, 1991, 254, 1497-1500.

[0077] Preferred embodiments of the invention are oligonucleotides with phosphorothioate backbones and oligonucleosides with heteroatom backbones, and in particular —CH₂—NH—O—CH₂—, —CH₂—N(CH₃)—O—CH₂—[known as a methylene (methylimino) or MMI backbone], —CH₂—O—N(CH₃)—CH₂—, —CH₂—N(CH₃)—N(CH₃)—CH₂— and —O—N(CH₃)—CH₂—CH₂— [wherein the native phosphodiester backbone is represented as —O—P—O—CH₂—] of the above referenced U.S. Pat. No. 5,489,677, and the amide backbones of the above referenced U.S. Pat. No. 5,602,240. Also preferred are oligonucleotides having morpholino backbone structures of the above-referenced U.S. Pat. No. 5,034,506.

[0078] Modified Sugars

[0079] Modified oligonucleotides may also contain one or more substituted sugar moieties. Preferred oligonucleotides comprise one of the following at the 2′ position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-alkyl-O-alkyl, wherein the alkyl, alkenyl and alkynyl may be substituted or unsubstituted C₁ to C₁₀ alkyl or C₂ to C₁₀ alkenyl and alkynyl. Particularly preferred are O[(CH₂)_(n)O]_(m)CH₃, O(CH₂)_(n)OCH₃, O(CH₂)_(n)NH₂, O(CH₂)_(n)CH₃, O(CH₂)_(n)ONH₂, and O(CH₂)_(n)ON[(CH₂)_(n)CH₃]₂, where n and m are from 1 to about 10. Other preferred oligonucleotides comprise one of the following at the 2′ position: C₁ to C₁₀ lower alkyl, substituted lower alkyl, alkenyl, alkynyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH₃, OCN, Cl, Br, CN, CF₃, OCF₃, SOCH₃, SO₂CH₃, ONO₂, NO₂, N₃, NH₂, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. A preferred modification includes 2′-methoxyethoxy (2′-O—CH₂CH₂OCH₃, also known as 2′-O-(2-methoxyethyl) or 2′-MOE) (Martin et al., Helv. Chim. Acta, 1995, 78, 486-504) i.e., an alkoxyalkoxy group. A further preferred modification includes 2′-dimethylaminooxyethoxy, i.e., a O(CH₂)₂ON(CH₃)₂ group, also known as 2′-DMAOE, as described in examples hereinbelow, and 2′-dimethylaminoethoxyethoxy (also known in the art as 2′-O-dimethyl-amino-ethoxy-ethyl or 2′-DMAEOE), i.e., 2′-O—CH₂—O—CH₂—N(CH₃)₂, also described in examples hereinbelow.

[0080] Other preferred modifications include 2′-methoxy (2′-O—CH₃), 2′-aminopropoxy (2′-OCH₂CH₂CH₂NH₂), 2′-allyl (2′-CH₂—CH═CH₂), 2′-O-allyl (2′-O—CH₂—CH═CH₂) and 2′-fluoro (2′-F) The 2′-modification may be in the arabino (up) position or ribo (down) position. A preferred 2′-arabino modification is 2′-F. Similar modifications may also be made at other positions on the oligonucleotide, particularly the 3′ position of the sugar on the 3′ terminal nucleotide or in 2′-5′ linked oligonucleotides and the 5′ position of 5′ terminal nucleotide. Oligonucleotides may also have sugar mimetics such as cyclobutyl moieties in place of the pentofuranosyl sugar Representative United States patents that teach the preparation of such modified sugar structures include, but are not limited to, U.S. Pat. Nos.: 4,981,957; 5,118,800; 5,319,080; 5,359,044; 5,393,878; 5,446,137; 5,466,786; 5,514,785; 5,519,134; 5,567,811; 5,576,427; 5,591,722; 5,597,909; 5,610,300; 5,627,053; 5,639,873; 5,646,265; 5,658,873; 5,670,633; 5,792,747; and 5,700,920, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.

[0081] A further preferred modification of the sugar includes Locked Nucleic Acids (LNAs) in which the 2′-hydroxyl group is linked to the 3′ or 4′ carbon atom of the sugar ring, thereby forming a bicyclic sugar moiety. The linkage is preferably a methylene (—CH₂—) n group bridging the 2′ oxygen atom and the 4′ carbon atom wherein n is 1 or 2. LNAs and preparation thereof are described in WO 98/39352 and WO 99/14226.

[0082] Natural and Modified Nucleobases

[0083] Oligonucleotides may also include nucleobase (often referred to in the art simply as “base”) modifications or substitutions. As used herein, “unmodified” or “natural” nucleobases include the purine bases adenine (A) and guanine (G), and the pyrimidine bases thymine (T), cytosine (C) and uracil (U). Modified nucleobases include other synthetic and natural nucleobases such as 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl (—C═C—CH₃) uracil and cytosine and other alkynyl derivatives of pyrimidine bases, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo particularly 5-bromo, 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine and 7-methyladenine, 2-F-adenine, 2-amino-adenine, 8-azaguanine and 8-azaadenine, 7-deazaguanine and 7-deazaadenine and 3-deazaguanine and 3-deazaadenine. Further modified nucleobases include tricyclic pyrimidines such as phenoxazine cytidine(1H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), phenothiazine cytidine (lH-pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one), G-clamps such as a substituted phenoxazine cytidine (e.g. 9-(2-aminoethoxy)-H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), carbazole cytidine (2H-pyrimido[4,5-b]indol-2-one), pyridoindole cytidine (H-pyrido[3′,2′:4,5]pyrrolo[2,3-d]pyrimidin-2-one). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza-adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, pages 858-859, Kroschwitz, J.I., ed. John Wiley & Sons, 1990, those disclosed by Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613, and those disclosed by Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, pages 289-302, Crooke, S. T. and Lebleu, B. ed., CRC Press, 1993. Certain of these nucleobases are particularly useful for increasing the binding affinity of the compounds of the invention. These include 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and O-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine. 5-methylcytosine substitutions have been shown to increase nucleic acid duplex stability by 0.6-1.2° C. and are presently preferred base substitutions, even more particularly when combined with 2′-O-methoxyethyl sugar modifications.

[0084] Representative United States patents that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include, but are not limited to, the above noted U.S. Pat. No. 3,687,808, as well as U.S. Pat. Nos.: 4,845,205; 5,130,302; 5,134,066; 5,175,273; 5,367,066; 5,432,272; 5,457,187; 5,459,255; 5,484,908; 5,502,177; 5,525,711; 5,552,540; 5,587,469; 5,594,121, 5,596,091; 5,614,617; 5,645,985; 5,830,653; 5,763,588; 6,005,096; and 5,681,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference, and U.S. Pat. No. 5,750,692, which is commonly owned with the instant application and also herein incorporated by reference.

[0085] Conjugates

[0086] Another modification of the oligonucleotides of the invention involves chemically linking to the oligonucleotide one or more moieties or conjugates which enhance the activity, cellular distribution or cellular uptake of the oligonucleotide. These moieties or conjugates can include conjugate groups covalently bound to functional groups such as primary or secondary hydroxyl groups. Conjugate groups of the invention include intercalators, reporter molecules, polyamines, polyamides, polyethylene glycols, polyethers, groups that enhance the pharmacodynamic properties of oligomers, and groups that enhance the pharmacokinetic properties of oligomers. Typical conjugate groups include cholesterols, lipids, phospholipids, biotin, phenazine, folate, phenanthridine, anthraquinone, acridine, fluores-ceins, rhodamines, coumarins, and dyes. Groups that enhance the pharmacodynamic properties, in the context of this invention, include groups that improve uptake, enhance resistance to degradation, and/or strengthen sequence-specific hybridization with the target nucleic acid. Groups that enhance the pharmacokinetic properties, in the context of this invention, include groups that improve uptake, distribution, metabolism or excretion of the compounds of the present invention. Representative conjugate groups are disclosed in International Patent Application PCT/US92/09196, filed Oct. 23, 1992, and U.S. Pat. No. 6,287,860, the entire disclosure of which are incorporated herein by reference. Conjugate moieties include but are not limited to lipid moieties such as a cholesterol moiety, cholic acid, a thioether, e.g., hexyl-S-tritylthiol, a thiocholesterol, an aliphatic chain, e.g., dodecandiol or undecyl residues, a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate, a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmityl moiety, or an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety. Oligonucleotides of the invention may also be conjugated to active drug substances, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fenbufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indomethicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic. Oligonucleotide-drug conjugates and their preparation are described in U.S. patent application Ser. No. 09/334,130 (filed Jun. 15, 1999) which is incorporated herein by reference in its entirety.

[0087] Representative United States patents that teach the preparation of such oligonucleotide conjugates include, but are not limited to, U.S. Pat. Nos.: 4,828,979; 4,948,882; 5,218,105; 5,525,465; 5,541,313; 5,545,730; 5,552,538; 5,578,717, 5,580,731; 5,580,731; 5,591,584; 5,109,124; 5,118,802; 5,138,045; 5,414,077; 5,486,603; 5,512,439; 5,578,718; 5,608,046; 4,587,044; 4,605,735; 4,667,025; 4,762,779; 4,789,737; 4,824,941; 4,835,263; 4,876,335; 4,904,582; 4,958,013; 5,082,830; 5,112,963; 5,214,136; 5,082,830; 5,112,963; 5,214,136; 5,245,022; 5,254,469; 5,258,506; 5,262,536; 5,272,250; 5,292,873; 5,317,098; 5,371,241, 5,391,723; 5,416,203, 5,451,463; 5,510,475; 5,512,667; 5,514,785; 5,565,552; 5,567,810; 5,574,142; 5,585,481; 5,587,371; 5,595,726; 5,597,696; 5,599,923; 5,599,928 and 5,688,941, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference.

[0088] Chimeric Compounds

[0089] It is not necessary for all positions in a given compound to be uniformly modified, and in fact more than one of the aforementioned modifications may be incorporated in a single compound or even at a single nucleoside within an oligonucleotide.

[0090] The present invention also includes antisense compounds which are chimeric compounds. “Chimeric” antisense compounds or “chimeras,” in the context of this invention, are antisense compounds, particularly oligonucleotides, which contain two or more chemically distinct regions, each made up of at least one monomer unit, i.e., a nucleotide in the case of an oligonucleotide compound. These oligonucleotides typically contain at least one region wherein the oligonucleotide is modified so as to confer upon the oligonucleotide increased resistance to nuclease degradation, increased cellular uptake, increased stability and/or increased binding affinity for the target nucleic acid. An additional region of the oligonucleotide may serve as a substrate for enzymes capable of cleaving RNA:DNA or RNA:RNA hybrids. By way of example, RNAse H is a cellular endonuclease which cleaves the RNA strand of an RNA:DNA duplex. Activation of RNase H, therefore, results in cleavage of the RNA target, thereby greatly enhancing the efficiency of oligonucleotide-mediated inhibition of gene expression. The cleavage of RNA:RNA hybrids can, in like fashion, be accomplished through the actions of endoribonucleases, such as RNAseL which cleaves both cellular and viral RNA. Cleavage of the RNA target can be routinely detected by gel electrophoresis and, if necessary, associated nucleic acid hybridization techniques known in the art.

[0091] Chimeric antisense compounds of the invention may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, oligonucleosides and/or oligonucleotide mimetics as described above. Such compounds have also been referred to in the art as hybrids or gapmers. Representative United States patents that teach the preparation of such hybrid structures include, but are not limited to, U.S. Pat. Nos.: 5,013,830; 5,149,797; 5,220,007; 5,256,775; 5,366,878; 5,403,711; 5,491,133; 5,565,350; 5,623,065; 5,652,355; 5,652,356; and 5,700,922, certain of which are commonly owned with the instant application, and each of which is herein incorporated by reference in its entirety.

[0092] G. Formulations

[0093] The compounds of the invention may also be admixed, encapsulated, conjugated or otherwise associated with other molecules, molecule structures or mixtures of compounds, as for example, liposomes, receptor-targeted molecules, oral, rectal, topical or other formulations, for assisting in uptake, distribution and/or absorption. Representative United States patents that teach the preparation of such uptake, distribution and/or absorption-assisting formulations include, but are not limited to, U.S. Pat. Nos.: 5,108,921; 5,354,844; 5,416,016; 5,459,127; 5,521,291; 5,543,158; 5,547,932; 5,583,020; 5,591,721; 4,426,330; 4,534,899; 5,013,556; 5,108,921; 5,213,804; 5,227,170; 5,264,221; 5,356,633; 5,395,619; 5,416,016; 5,417,978; 5,462,854; 5,469,854; 5,512,295; 5,527,528; 5,534,259; 5,543,152; 5,556,948; 5,580,575; and 5,595,756, each of which is herein incorporated by reference.

[0094] The antisense compounds of the invention encompass any pharmaceutically acceptable salts, esters, or salts of such esters, or any other compound which, upon administration to an animal, including a human, is capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to prodrugs and pharmaceutically acceptable salts of the compounds of the invention, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents.

[0095] The term “prodrug” indicates a therapeutic agent that is prepared in an inactive form that is converted to an active form (i.e., drug) within the body or cells thereof by the action of endogenous enzymes or other chemicals and/or conditions. In particular, prodrug versions of the oligonucleotides of the invention are prepared as SATE [(S-acetyl-2-thioethyl) phosphate] derivatives according to the methods disclosed in WO 93/24510 to Gosselin et al., published Dec. 9, 1993 or in WO 94/26764 and U.S. Pat. No. 5,770,713 to Imbach et al.

[0096] The term “pharmaceutically acceptable salts” refers to physiologically and pharmaceutically acceptable salts of the compounds of the invention: i.e., salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto. For oligonucleotides, preferred examples of pharmaceutically acceptable salts and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety.

[0097] The present invention also includes pharmaceutical compositions and formulations which include the antisense compounds of the invention. The pharmaceutical compositions of the present invention may be administered in a number of ways depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including ophthalmic and to mucous membranes including vaginal and rectal delivery), pulmonary, e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal, intranasal, epidermal and transdermal), oral or parenteral. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Oligonucleotides with at least one 2′-O-methoxyethyl modification are believed to be particularly useful for oral administration. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable. Coated condoms, gloves and the like may also be useful.

[0098] The pharmaceutical formulations of the present invention, which may conveniently be presented in unit dosage form, may be prepared according to conventional techniques well known in the pharmaceutical industry. Such techniques include the step of bringing into association the active ingredients with the pharmaceutical carrier(s) or excipient(s). In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredients with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

[0099] The compositions of the present invention may be formulated into any of many possible dosage forms such as, but not limited to, tablets, capsules, gel capsules, liquid syrups, soft gels, suppositories, and enemas. The compositions of the present invention may also be formulated as suspensions in aqueous, non-aqueous or mixed media. Aqueous suspensions may further contain substances which increase the viscosity of the suspension including, for example, sodium carboxymethylcellulose, sorbitol and/or dextran. The suspension may also contain stabilizers.

[0100] Pharmaceutical compositions of the present invention include, but are not limited to, solutions, emulsions, foams and liposome-containing formulations. The pharmaceutical compositions and formulations of the present invention may comprise one or more penetration enhancers, carriers, excipients or other active or inactive ingredients.

[0101] Emulsions are typically heterogenous systems of one liquid dispersed in another in the form of droplets usually exceeding 0.1 μm in diameter. Emulsions may contain additional components in addition to the dispersed phases, and the active drug which may be present as a solution in either the aqueous phase, oily phase or itself as a separate phase. Microemulsions are included as an embodiment of the present invention. Emulsions and their uses are well known in the art and are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety.

[0102] Formulations of the present invention include liposomal formulations. As used in the present invention, the term “liposome” means a vesicle composed of amphiphilic lipids arranged in a spherical bilayer or bilayers. Liposomes are unilamellar or multilamellar vesicles which have a membrane formed from a lipophilic material and an aqueous interior that contains the composition to be delivered. Cationic liposomes are positively charged liposomes which are believed to interact with negatively charged DNA molecules to form a stable complex. Liposomes that are pH-sensitive or negatively-charged are believed to entrap DNA rather than complex with it. Both cationic and noncationic liposomes have been used to deliver DNA to cells.

[0103] Liposomes also include “sterically stabilized” liposomes, a term which, as used herein, refers to liposomes comprising one or more specialized lipids that, when incorporated into liposomes, result in enhanced circulation lifetimes relative to liposomes lacking such specialized lipids. Examples of sterically stabilized liposomes are those in which part of the vesicle-forming lipid portion of the liposome comprises one or more glycolipids or is derivatized with one or more hydrophilic polymers, such as a polyethylene glycol (PEG) moiety. Liposomes and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety.

[0104] The pharmaceutical formulations and compositions of the present invention may also include surfactants. The use of surfactants in drug products, formulations and in emulsions is well known in the art. Surfactants and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety.

[0105] In one embodiment, the present invention employs various penetration enhancers to effect the efficient delivery of nucleic acids, particularly oligonucleotides. In addition to aiding the diffusion of non-lipophilic drugs across cell membranes, penetration enhancers also enhance the permeability of lipophilic drugs. Penetration enhancers may be classified as belonging to one of five broad categories, i.e., surfactants, fatty acids, bile salts, chelating agents, and non-chelating non-surfactants. Penetration enhancers and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety.

[0106] One of skill in the art will recognize that formulations are routinely designed according to their intended use, i.e. route of administration.

[0107] Preferred formulations for topical administration include those in which the oligonucleotides of the invention are in admixture with a topical delivery agent such as lipids, liposomes, fatty acids, fatty acid esters, steroids, chelating agents and surfactants. Preferred lipids and liposomes include neutral (e.g. dioleoylphosphatidyl DOPE ethanolamine, dimyristoylphosphatidyl choline DMPC, distearolyphosphatidyl choline) negative (e.g. dimyristoylphosphatidyl glycerol DMPG) and cationic (e.g. dioleoyltetramethylaminopropyl DOTAP and dioleoylphosphatidyl ethanolamine DOTMA).

[0108] For topical or other administration, oligonucleotides of the invention may be encapsulated within liposomes or may form complexes thereto, in particular to cationic liposomes. Alternatively, oligonucleotides may be complexed to lipids, in particular to cationic lipids. Preferred fatty acids and esters, pharmaceutically acceptable salts thereof, and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety. Topical formulations are described in detail in U.S. patent application Ser. No. 09/315,298 filed on May 20, 1999, which is incorporated herein by reference in its entirety.

[0109] Compositions and formulations for oral administration include powders or granules, microparticulates, nanoparticulates, suspensions or solutions in water or non-aqueous media, capsules, gel capsules, sachets, tablets or minitablets. Thickeners, flavoring agents, diluents, emulsifiers, dispersing aids or binders may be desirable. Preferred oral formulations are those in which oligonucleotides of the invention are administered in conjunction with one or more penetration enhancers surfactants and chelators. Preferred surfactants include fatty acids and/or esters or salts thereof, bile acids and/or salts thereof. Preferred bile acids/salts and fatty acids and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety. Also preferred are combinations of penetration enhancers, for example, fatty acids/salts in combination with bile acids/salts. A particularly preferred combination is the sodium salt of lauric acid, capric acid and UDCA. Further penetration enhancers include polyoxyethylene-9-lauryl ether, polyoxyethylene-20-cetyl ether. Oligonucleotides of the invention may be delivered orally, in granular form including sprayed dried particles, or complexed to form micro or nanoparticles. Oligonucleotide complexing agents and their uses are further described in U.S. Pat. No. 6,287,860, which is incorporated herein in its entirety. Oral formulations for oligonucleotides and their preparation are described in detail in U.S. application Ser. Nos. 09/108,673 (filed Jul. 1, 1998), 09/315,298 (filed May 20, 1999) and 10/071,822, filed Feb. 8, 2002, each of which is incorporated herein by reference in their entirety.

[0110] Compositions and formulations for parenteral, intra-thecal or intraventricular administration may include sterile aqueous solutions which may also contain buffers, diluents and other suitable additives such as, but not limited to, penetration enhancers, carrier compounds and other pharmaceutically acceptable carriers or excipients.

[0111] Certain embodiments of the invention provide pharmaceutical compositions containing one or more oligomeric compounds and one or more other chemotherapeutic agents which function by a non-antisense mechanism. Examples of such chemotherapeutic agents include but are not limited to cancer chemotherapeutic drugs such as daunorubicin, daunomycin, dactinomycin, doxorubicin, epirubicin, idarubicin, esorubicin, bleomycin, mafosfamide, ifosfamide, cytosine ara-binoside, bis-chloroethylnitrosurea, busulfan, mitomycin C, actinomycin D, mithramycin, prednisone, hydroxyprogesterone, testosterone, tamoxifen, dacarbazine, procarbazine, hexamethylmelamine, pentamethylmelamine, mitoxantrone, amsacrine, chlorambucil, methylcyclohexylnitrosurea, nitrogen mustards, melphalan, cyclophosphamide, 6-mercaptopurine, 6-thioguanine, cytarabine, 5-azacytidine, hydroxyurea, deoxyco-formycin, 4-hydroxyperoxycyclophosphoramide, 5-fluorouracil (5-FU), 5-fluorodeoxyuridine (5-FUdR), methotrexate (MTX), colchicine, taxol, vincristine, vinblastine, etoposide (VP-16), trimetrexate, irinotecan, topotecan, gemcitabine, teni-poside, cisplatin and diethylstilbestrol (DES). When used with the compounds of the invention, such chemotherapeutic agents may be used individually (e.g., 5-FU and oligonucleotide), sequentially (e.g., 5-FU and oligonucleotide for a period of time followed by MTX and oligonucleotide), or in combination with one or more other such chemotherapeutic agents (e.g., 5-FU, MTX and oligonucleotide, or 5-FU, radiotherapy and oligonucleotide). Anti-inflammatory drugs, including but not limited to nonsteroidal anti-inflammatory drugs and corticosteroids, and antiviral drugs, including but not limited to ribivirin, vidarabine, acyclovir and ganciclovir, may also be combined in compositions of the invention. Combinations of antisense compounds and other non-antisense drugs are also within the scope of this invention. Two or more combined compounds may be used together or sequentially.

[0112] In another related embodiment, compositions of the invention may contain one or more antisense compounds, particularly oligonucleotides, targeted to a first nucleic acid and one or more additional antisense compounds targeted to a second nucleic acid target. Alternatively, compositions of the invention may contain two or more antisense compounds targeted to different regions of the same nucleic acid target. Numerous examples of antisense compounds are known in the art. Two or more combined compounds may be used together or sequentially.

[0113] H. Dosing

[0114] The formulation of therapeutic compositions and their subsequent administration (dosing) is believed to be within the skill of those in the art. Dosing is dependent on severity and responsiveness of the disease state to be treated, with the course of treatment lasting from several days to several months, or until a cure is effected or a diminution of the disease state is achieved. Optimal dosing schedules can be calculated from measurements of drug accumulation in the body of the patient. Persons of ordinary skill can easily determine optimum dosages, dosing methodologies and repetition rates. Optimum dosages may vary depending on the relative potency of individual oligonucleotides, and can generally be estimated based on EC₅₀s found to be effective in in vitro and in vivo animal models. In general, dosage is from 0.01 ug to 100 g per kg of body weight, and may be given once or more daily, weekly, monthly or yearly, or even once every 2 to 20 years. Persons of ordinary skill in the art can easily estimate repetition rates for dosing based on measured residence times and concentrations of the drug in bodily fluids or tissues. Following successful treatment, it may be desirable to have the patient undergo maintenance therapy to prevent the recurrence of the disease state, wherein the oligonucleotide is administered in maintenance doses, ranging from 0.01 ug to 100 g per kg of body weight, once or more daily, to once every 20 years.

[0115] While the present invention has been described with specificity in accordance with certain of its preferred embodiments, the following examples serve only to illustrate the invention and are not intended to limit the same.

EXAMPLES Example 1

[0116] Synthesis of Nucleoside Phosphoramidites

[0117] The following compounds, including amidites and their intermediates were prepared as described in U.S. Pat. No. 6,426,220 and published PCT WO 02/36743; 5′-O-Dimethoxytrityl-thymidine intermediate for 5-methyl dC amidite, 5′-O-Dimethoxytrityl-2′-deoxy-5-methylcytidine intermediate for 5-methyl-dC amidite, 5′-O-Dimethoxytrityl-2′-deoxy-N4-benzoyl-5-methylcytidine penultimate intermediate for 5-methyl dC amidite, [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-deoxy-N⁴-benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (5-methyl dC amidite), 2′-Fluorodeoxyadenosine, 2′-Fluorodeoxyguanosine, 2′-Fluorouridine, 2′-Fluorodeoxycytidine, 2′-O-(2-Methoxyethyl) modified amidites, 2′-O-(2-methoxyethyl)-5-methyluridine intermediate, 5′-O-DMT-2′-O-(2-methoxyethyl)-5-methyluridine penultimate intermediate, [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-5-methyluridin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE T amidite), 5′-O-Dimethoxytrityl-2′-O-(2-methoxyethyl)-5-methylcytidine intermediate, 5′-O-dimethoxytrityl-2′-O-(2-methoxyethyl)-N⁴-benzoyl-5-methyl-cytidine penultimate intermediate, [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N⁴-benzoyl-5-methylcytidin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE 5-Me-C amidite), [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N⁶-benzoyladenosin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE A amdite), [5′-O-(4,4′-Dimethoxytriphenylmethyl)-2′-O-(2-methoxyethyl)-N⁴-isobutyrylguanosin-3′-O-yl]-2-cyanoethyl-N,N-diisopropylphosphoramidite (MOE G amidite), 2′-O-(Aminooxyethyl) nucleoside amidites and 2′-O-(dimethylamino-oxyethyl) nucleoside amidites, 2′-(Dimethylaminooxyethoxy) nucleoside amidites, 5′-O-tert-Butyldiphenylsilyl-O²-2′-anhydro-5-methyluridine , 5′-O-tert-Butyldiphenylsilyl-2′-O-(2-hydroxyethyl)-5-methyluridine, 2′-O-([2-phthalimidoxy)ethyl]-5′-t-butyldiphenylsilyl-5-methyluridine , 5′-O-tert-butyldiphenylsilyl-2′-O-[(2-formadoximinooxy)ethyl]-5-methyluridine, 5′-O-tert-Butyldiphenylsilyl-2′-O-[N,N dimethylaminooxyethyl]-5-methyluridine, 2′-O-(dimethylaminooxyethyl)-5-methyluridine, 5′-O-DMT-2′-O-(dimethylaminooxyethyl)-5-methyluridine, 5′-O-DMT-2′-O-(2-N,N-dimethylaminooxyethyl)-5-methyluridine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite], 2′-(Aminooxyethoxy) nucleoside amidites, N2-isobutyryl-6-O-diphenylcarbamoyl-2′-O-(2-ethylacetyl)-5′-O-(4,4′-dimethoxytrityl)guanosine-3′-[(2-cyanoethyl)-N,N-diisopropylphosphoramidite], 2′-dimethylaminoethoxyethoxy (2′-DMAEOE) nucleoside amidites, 2′-O-[2(2-N,N-dimethylaminoethoxy)ethyl]-5-methyl uridine, 5′-O-dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)-ethyl)]-5-methyl uridine and 5′-O-Dimethoxytrityl-2′-O-[2(2-N,N-dimethylaminoethoxy)-ethyl)]-5-methyl uridine-3′-O-(cyanoethyl-N,N-diisopropyl)phosphoramidite.

Example 2

[0118] Oligonucleotide and Oligonucleoside Synthesis

[0119] The antisense compounds used in accordance with this invention may be conveniently and routinely made through the well-known technique of solid phase synthesis. Equipment for such synthesis is sold by several vendors including, for example, Applied Biosystems (Foster City, Calif.). Any other means for such synthesis known in the art may additionally or alternatively be employed. It is well known to use similar techniques to prepare oligonucleotides such as the phosphorothioates and alkylated derivatives.

[0120] Oligonucleotides: Unsubstituted and substituted phosphodiester (P═O) oligonucleotides are synthesized on an automated DNA synthesizer (Applied Biosystems model 394) using standard phosphoramidite chemistry with oxidation by iodine.

[0121] Phosphorothioates (P═S) are synthesized similar to phosphodiester oligonucleotides with the following exceptions: thiation was effected by utilizing a 10% w/v solution of 3,H-1,2-benzodithiole-3-one 1,1-dioxide in acetonitrile for the oxidation of the phosphite linkages. The thiation reaction step time was increased to 180 sec and preceded by the normal capping step. After cleavage from the CPG column and deblocking in concentrated ammonium hydroxide at 55° C. (12-16 hr), the oligonucleotides were recovered by precipitating with >3 volumes of ethanol from a 1 M NH₄OAc solution. Phosphinate oligonucleotides are prepared as described in U.S. Pat. No. 5,508,270, herein incorporated by reference.

[0122] Alkyl phosphonate oligonucleotides are prepared as described in U.S. Pat. No. 4,469,863, herein incorporated by reference.

[0123] 3′-Deoxy-3′-methylene phosphonate oligonucleotides are prepared as described in U.S. Pat. Nos. 5,610,289 or 5,625,050, herein incorporated by reference.

[0124] Phosphoramidite oligonucleotides are prepared as described in U.S. Pat. No., 5,256,775 or U.S. Pat. No. 5,366,878, herein incorporated by reference.

[0125] Alkylphosphonothioate oligonucleotides are prepared as described in published PCT applications PCT/US94/00902 and PCT/US93/06976 (published as WO 94/17093 and WO 94/02499, respectively), herein incorporated by reference.

[0126] 3′-Deoxy-3′-amino phosphoramidate oligonucleotides are prepared as described in U.S. Pat. No. 5,476,925, herein incorporated by reference.

[0127] Phosphotriester oligonucleotides are prepared as described in U.S. Pat. No. 5,023,243, herein incorporated by reference.

[0128] Borano phosphate oligonucleotides are prepared as described in U.S. Pat. Nos. 5,130,302 and 5,177,198, both herein incorporated by reference.

[0129] Oligonucleosides: Methylenemethylimino linked oligonucleosides, also identified as MMI linked oligonucleosides, methylenedimethylhydrazo linked oligonucleosides, also identified as MDH linked oligonucleosides, and methylenecarbonylamino linked oligonucleosides, also identified as amide-3 linked oligonucleosides, and methyleneaminocarbonyl linked oligonucleosides, also identified as amide-4 linked oligonucleosides, as well as mixed backbone compounds having, for instance, alternating MMI and P═O or P═S linkages are prepared as described in U.S. Pat. Nos. 5,378,825, 5,386,023, 5,489,677, 5,602,240 and 5,610,289, all of which are herein incorporated by reference.

[0130] Formacetal and thioformacetal linked oligonucleosides are prepared as described in U.S. Pat. Nos. 5,264,562 and 5,264,564, herein incorporated by reference.

[0131] Ethylene oxide linked oligonucleosides are prepared as described in U.S. Pat. No. 5,223,618, herein incorporated by reference.

Example 3

[0132] RNA Synthesis

[0133] In general, RNA synthesis chemistry is based on the selective incorporation of various protecting groups at strategic intermediary reactions. Although one of ordinary skill in the art will understand the use of protecting groups in organic synthesis, a useful class of protecting groups includes silyl ethers. In particular bulky silyl ethers are used to protect the 5′-hydroxyl in combination with an acid-labile orthoester protecting group on the 2′-hydroxyl. This set of protecting groups is then used with standard solid-phase synthesis technology. It is important to lastly remove the acid labile orthoester protecting group after all other synthetic steps. Moreover, the early use of the silyl protecting groups during synthesis ensures facile removal when desired, without undesired deprotection of 2′hydroxyl.

[0134] Following this procedure for the sequential protection of the 5′-hydroxyl in combination with protection of the 2′-hydroxyl by protecting groups that are differentially removed and are differentially chemically labile, RNA oligonucleotides were synthesized.

[0135] RNA oligonucleotides are synthesized in a stepwise fashion. Each nucleotide is added sequentially (3′- to 5′-direction) to a solid support-bound oligonucleotide. The first nucleoside at the 3′-end of the chain is covalently attached to a solid support. The nucleotide precursor, a ribonucleoside phosphoramidite, and activator are added, coupling the second base onto the 5′-end of the first nucleoside. The support is washed and any unreacted 5′-hydroxyl groups are capped with acetic anhydride to yield 5′-acetyl moieties. The linkage is then oxidized to the more stable and ultimately desired P(V) linkage. At the end of the nucleotide addition cycle, the 5′-silyl group is cleaved with fluoride. The cycle is repeated for each subsequent nucleotide.

[0136] Following synthesis, the methyl protecting groups on the phosphates are cleaved in 30 minutes utilizing 1 M disodium-2-carbamoyl-2-cyanoethylene-1,1-dithiolate trihydrate (S₂Na₂) in DMF. The deprotection solution is washed from the solid support-bound oligonucleotide using water. The support is then treated with 40% methylamine in water for 10 minutes at 55° C. This releases the RNA oligonucleotides into solution, deprotects the exocyclic amines, and modifies the 2′- groups. The oligonucleotides can be analyzed by anion exchange HPLC at this stage.

[0137] The 2′-orthoester groups are the last protecting groups to be removed. The ethylene glycol monoacetate orthoester protecting group developed by Dharmacon Research, Inc. (Lafayette, Colo.), is one example of a useful orthoester protecting group which, has the following important properties. It is stable to the conditions of nucleoside phosphoramidite synthesis and oligonucleotide synthesis. However, after oligonucleotide synthesis the oligonucleotide is treated with methylamine which not only cleaves the oligonucleotide from the solid support but also removes the acetyl groups from the orthoesters. The resulting 2-ethyl-hydroxyl substituents on the orthoester are less electron withdrawing than the acetylated precursor. As a result, the modified orthoester becomes more labile to acid-catalyzed hydrolysis. Specifically, the rate of cleavage is approximately 10 times faster after the acetyl groups are removed. Therefore, this orthoester possesses sufficient stability in order to be compatible with oligonucleotide synthesis and yet, when subsequently modified, permits deprotection to be carried out under relatively mild aqueous conditions compatible with the final RNA oligonucleotide product.

[0138] Additionally, methods of RNA synthesis are well known in the art (Scaringe, S. A. Ph.D. Thesis, University of Colorado, 1996; Scaringe, S. A., et al., J. Am. Chem. Soc., 1998, 120, 11820-11821; Matteucci, M. D. and Caruthers, M. H. J. Am. Chem. Soc., 1981, 103, 3185-3191; Beaucage, S. L. and Caruthers, M. H. Tetrahedron Lett., 1981, 22, 1859-1862; Dahl, B. J., et al., Acta Chem. Scand,. 1990, 44, 639-641; Reddy, M. P., et al., Tetrahedrom Lett., 1994, 25, 4311-4314; Wincott, F. et al., Nucleic Acids Res., 1995, 23, 2677-2684; Griffin, B. E., et al., Tetrahedron, 1967, 23, 2301-2313; Griffin, B. E., et al., Tetrahedron, 1967, 23, 2315-2331).

[0139] RNA antisense compounds (RNA oligonucleotides) of the present invention can be synthesized by the methods herein or purchased from Dharmacon Research, Inc (Lafayette, Colo.). Once synthesized, complementary RNA antisense compounds can then be annealed by methods known in the art to form double stranded (duplexed) antisense compounds. For example, duplexes can be formed by combining 30 μl of each of the complementary strands of RNA oligonucleotides (50 uM RNA oligonucleotide solution) and 15 μl of 5× annealing buffer (100 mM potassium acetate, 30 mM HEPES-KOH pH 7.4, 2 mM magnesium acetate) followed by heating for 1 minute at 90° C., then 1 hour at 37° C. The resulting duplexed antisense compounds can be used in kits, assays, screens, or other methods to investigate the role of a target nucleic acid.

Example 4

[0140] Synthesis of Chimeric Oligonucleotides

[0141] Chimeric oligonucleotides, oligonucleosides or mixed oligonucleotides/oligonucleosides of the invention can be of several different types. These include a first type wherein the “gap” segment of linked nucleosides is positioned between 5′ and 3′ “wing” segments of linked nucleosides and a second “open end” type wherein the “gap” segment is located at either the 3′ or the 5′ terminus of the oligomeric compound. Oligonucleotides of the first type are also known in the art as “gapmers” or gapped oligonucleotides. Oligonucleotides of the second type are also known in the art as “hemimers” or “wingmers”.

[0142] [2′-O—Me]—[2′-deoxy]—[2′-O—Me] Chimeric Phosphorothioate Oligonucleotides

[0143] Chimeric oligonucleotides having 2′-O-alkyl phosphorothioate and 2′-deoxy phosphorothioate oligonucleotide segments are synthesized using an Applied Biosystems automated DNA synthesizer Model 394, as above. Oligonucleotides are synthesized using the automated synthesizer and 2′-deoxy-5′-dimethoxytrityl-3′-O-phosphoramidite for the DNA portion and 5′-dimethoxytrityl-2′-O-methyl-3′-O-phosphoramidite for 5′ and 3′ wings. The standard synthesis cycle is modified by incorporating coupling steps with increased reaction times for the 5′-dimethoxytrityl-2′-O-methyl-3′-O-phosphoramidite. The fully protected oligonucleotide is cleaved from the support and deprotected in concentrated ammonia (NH₄OH) for 12-16 hr at 55° C. The deprotected oligo is then recovered by an appropriate method (precipitation, column chromatography, volume reduced in vacuo and analyzed spetrophotometrically for yield and for purity by capillary electrophoresis and by mass spectrometry.

[0144] [2′-O-(2-Methoxyethyl)]—[2′-deoxy]—[2′-O-(Methoxyethyl)] Chimeric Phosphorothioate Oligonucleotides

[0145] [2′-O-(2-methoxyethyl)]—[2′-deoxy]—[-2′-O-(methoxyethyl)] chimeric phosphorothioate oligonucleotides were prepared as per the procedure above for the 2′-O-methyl chimeric oligonucleotide, with the substitution of 2′-O-(methoxyethyl) amidites for the 2′-O-methyl amidites.

[0146] [2′-O-(2-Methoxyethyl)Phosphodiester]—[2′-deoxy Phosphorothioate]—[2′-O-(2-Methoxyethyl) Phosphodiester] Chimeric Oligonucleotides

[0147] [2′-O-(2-methoxyethyl phosphodiester]—[2′-deoxy phosphorothioate]—[2′-O-(methoxyethyl) phosphodiester] chimeric oligonucleotides are prepared as per the above procedure for the 2′-O-methyl chimeric oligonucleotide with the substitution of 2′-O-(methoxyethyl) amidites for the 2′-O-methyl amidites, oxidation with iodine to generate the phosphodiester internucleotide linkages within the wing portions of the chimeric structures and sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) to generate the phosphorothioate internucleotide linkages for the center gap.

[0148] Other chimeric oligonucleotides, chimeric oligonucleosides and mixed chimeric oligonucleotides/oligonucleosides are synthesized according to U.S. Pat. No. 5,623,065, herein incorporated by reference.

Example 5

[0149] Design and Screening of Duplexed Antisense Compounds Targeting Fetoprotein Transcription Factor

[0150] In accordance with the present invention, a series of nucleic acid duplexes comprising the antisense compounds of the present invention and their complements can be designed to target fetoprotein transcription factor. The nucleobase sequence of the antisense strand of the duplex comprises at least a portion of an oligonucleotide in Table 1. The ends of the strands may be modified by the addition of one or more natural or modified nucleobases to form an overhang. The sense strand of the dsRNA is then designed and synthesized as the complement of the antisense strand and may also contain modifications or additions to either terminus. For example, in one embodiment, both strands of the dsRNA duplex would be complementary over the central nucleobases, each having overhangs at one or both termini.

[0151] For example, a duplex comprising an antisense strand having the sequence CGAGAGGCGGACGGGACCG and having a two-nucleobase overhang of deoxythymidine(dT) would have the following structure:   cgagaggcggacgggaccgTT Antisense Strand   ||||||||||||||||||| TTgctctccgcctgccctggc Complement

[0152] RNA strands of the duplex can be synthesized by methods disclosed herein or purchased from Dharmacon Research Inc., (Lafayette, Colo.). Once synthesized, the complementary strands are annealed. The single strands are aliquoted and diluted to a concentration of 50 uM. Once diluted, 30 uL of each strand is combined with 15 uL of a 5× solution of annealing buffer. The final concentration of said buffer is 100 mM potassium acetate, 30 mM HEPES-KOH pH 7.4, and 2mM magnesium acetate. The final volume is 75 uL. This solution is incubated for 1 minute at 90° C. and then centrifuged for 15 seconds. The tube is allowed to sit for 1 hour at 37° C. at which time the dsRNA duplexes are used in experimentation. The final concentration of the dsRNA duplex is 20 uM. This solution can be stored frozen (−20° C.) and freeze-thawed up to 5 times.

[0153] Once prepared, the duplexed antisense compounds are evaluated for their ability to modulate fetoprotein transcription factor expression.

[0154] When cells reached 80% confluency, they are treated with duplexed antisense compounds of the invention. For cells grown in 96-well plates, wells are washed once with 200 μL OPTI-MEM-1 reduced-serum medium (Gibco BRL) and then treated with 130 μL of OPTI-MEM-1 containing 12 μg/mL LIPOFECTIN (Gibco BRL) and the desired duplex antisense compound at a final concentration of 200 nM. After 5 hours of treatment, the medium is replaced with fresh medium. Cells are harvested 16 hours after treatment, at which time RNA is isolated and target reduction measured by RT-PCR.

Example 6

[0155] Oligonucleotide Isolation

[0156] After cleavage from the controlled pore glass solid support and deblocking in concentrated ammonium hydroxide at 55° C. for 12-16 hours, the oligonucleotides or oligonucleosides are recovered by precipitation out of 1 M NH₄OAc with >3 volumes of ethanol. Synthesized oligonucleotides were analyzed by electrospray mass spectroscopy (molecular weight determination) and by capillary gel electrophoresis and judged to be at least 70% full length material. The relative amounts of phosphorothioate and phosphodiester linkages obtained in the synthesis was determined by the ratio of correct molecular weight relative to the −16 amu product (+/−32 +/−48). For some studies oligonucleotides were purified by HPLC, as described by Chiang et al., J. Biol. Chem. 1991, 266, 18162-18171. Results obtained with HPLC-purified material were similar to those obtained with non-HPLC purified material.

Example 7

[0157] Oligonucleotide Synthesis—96 Well Plate Format

[0158] Oligonucleotides were synthesized via solid phase P(III) phosphoramidite chemistry on an automated synthesizer capable of assembling 96 sequences simultaneously in a 96-well format. Phosphodiester internucleotide linkages were afforded by oxidation with aqueous iodine. Phosphorothioate internucleotide linkages were generated by sulfurization utilizing 3,H-1,2 benzodithiole-3-one 1,1 dioxide (Beaucage Reagent) in anhydrous acetonitrile. Standard base-protected beta-cyanoethyl-diiso-propyl phosphoramidites were purchased from commercial vendors (e.g. PE-Applied Biosystems, Foster City, Calif., or Pharmacia, Piscataway, N.J.). Non-standard nucleosides are synthesized as per standard or patented methods. They are utilized as base protected beta-cyanoethyldiisopropyl phosphoramidites.

[0159] Oligonucleotides were cleaved from support and deprotected with concentrated NH₄OH at elevated temperature (55-60° C.) for 12-16 hours and the released product then dried in vacuo. The dried product was then re-suspended in sterile water to afford a master plate from which all analytical and test plate samples are then diluted utilizing robotic pipettors.

Example 8

[0160] Oligonucleotide Analysis—96-Well Plate Format

[0161] The concentration of oligonucleotide in each well was assessed by dilution of samples and UV absorption spectroscopy. The full-length integrity of the individual products was evaluated by capillary electrophoresis (CE) in either the 96-well format (Beckman P/ACE™ MDQ) or, for individually prepared samples, on a commercial CE apparatus (e.g., Beckman P/ACE™ 5000, ABI 270). Base and backbone composition was confirmed by mass analysis of the compounds utilizing electrospray-mass spectroscopy. All assay test plates were diluted from the master plate using single and multi-channel robotic pipettors. Plates were judged to be acceptable if at least 85% of the compounds on the plate were at least 85% full length.

Example 9

[0162] Cell Culture and Oligonucleotide Treatment

[0163] The effect of antisense compounds on target nucleic acid expression can be tested in any of a variety of cell types provided that the target nucleic acid is present at measurable levels. This can be routinely determined using, for example, PCR or Northern blot analysis. The following cell types are provided for illustrative purposes, but other cell types can be routinely used, provided that the target is expressed in the cell type chosen. This can be readily determined by methods routine in the art, for example Northern blot analysis, ribonuclease protection assays, or RT-PCR.

[0164] T-24 cells:

[0165] The human transitional cell bladder carcinoma cell line T-24 was obtained from the American Type Culture Collection (ATCC) (Manassas, Va.). T-24 cells were routinely cultured in complete McCoy's 5A basal media (Invitrogen Corporation, Carlsbad, Calif.) supplemented with 10% fetal calf serum (Invitrogen Corporation, Carlsbad, Calif.), penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Invitrogen Corporation, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached 90% confluence. Cells were seeded into 96-well plates (Falcon-Primaria #353872) at a density of 7000 cells/well for use in RT-PCR analysis.

[0166] For Northern blotting or other analysis, cells may be seeded onto 100 mm or other standard tissue culture plates and treated similarly, using appropriate volumes of medium and oligonucleotide.

[0167] A549 cells:

[0168] The human lung carcinoma cell line A549 was obtained from the American Type Culture Collection (ATCC) (Manassas, Va.). A549 cells were routinely cultured in DMEM basal media (Invitrogen Corporation, Carlsbad, Calif.) supplemented with 10% fetal calf serum (Invitrogen Corporation, Carlsbad, Calif.), penicillin 100 units per mL, and streptomycin 100 micrograms per mL (Invitrogen Corporation, Carlsbad, Calif.). Cells were routinely passaged by trypsinization and dilution when they reached 90% confluence.

[0169] NHDF cells:

[0170] Human neonatal dermal fibroblast (NHDF) were obtained from the Clonetics Corporation (Walkersville, Md.). NHDFs were routinely maintained in Fibroblast Growth Medium (Clonetics Corporation, Walkersville, Md.) supplemented as recommended by the supplier. Cells were maintained for up to 10 passages as recommended by the supplier.

[0171] HEK cells:

[0172] Human embryonic keratinocytes (HEK) were obtained from the Clonetics Corporation (Walkersville, Md.). HEKs were routinely maintained in Keratinocyte Growth Medium (Clonetics Corporation, Walkersville, Md.) formulated as recommended by the supplier. Cells were routinely maintained for up to 10 passages as recommended by the supplier.

[0173] Treatment with Antisense Compounds:

[0174] When cells reached 65-75% confluency, they were treated with oligonucleotide. For cells grown in 96-well plates, wells were washed once with 100 μL OPTI-MEM™-1 reduced-serum medium (Invitrogen Corporation, Carlsbad, Calif.) and then treated with 130 FL of OPTI-MEMTm-1 containing 3.75 gg/mL LIPOFECTIN™ (Invitrogen Corporation, Carlsbad, Calif.) and the desired concentration of oligonucleotide. Cells are treated and data are obtained in triplicate. After 4-7 hours of treatment at 37° C., the medium was replaced with fresh medium. Cells were harvested 16-24 hours after oligonucleotide treatment.

[0175] The concentration of oligonucleotide used varies from cell line to cell line. To determine the optimal oligonucleotide concentration for a particular cell line, the cells are treated with a positive control oligonucleotide at a range of concentrations. For human cells the positive control oligonucleotide is selected from either ISIS 13920 (TCCGTCATCGCTCCTCAGGG, SEQ ID NO: 1) which is targeted to human H-ras, or ISIS 18078, (GTGCGCGCGAGCCCGAAATC, SEQ ID NO: 2) which is targeted to human Jun-N-terminal kinase-2 (JNK2). Both controls are 2′-O-methoxyethyl gapmers (2′-O-methoxyethyls shown in bold) with a phosphorothioate backbone. For mouse or rat cells the positive control oligonucleotide is ISIS 15770, ATGCATTCTGCCCCCAAGGA, SEQ ID NO: 3, a 2′-O-methoxyethyl gapmer (2′-O-methoxyethyls shown in bold) with a phosphorothioate backbone which is targeted to both mouse and rat c-raf. The concentration of positive control oligonucleotide that results in 80% inhibition of c-H-ras (for ISIS 13920), JNK2 (for ISIS 18078) or c-raf (for ISIS 15770) mRNA is then utilized as the screening concentration for new oligonucleotides in subsequent experiments for that cell line. If 80% inhibition is not achieved, the lowest concentration of positive control oligonucleotide that results in 60% inhibition of c-H-ras, JNK2 or c-raf mRNA is then utilized as the oligonucleotide screening concentration in subsequent experiments for that cell line. If 60% inhibition is not achieved, that particular cell line is deemed as unsuitable for oligonucleotide transfection experiments. The concentrations of antisense oligonucleotides used herein are from 50 nM to 300 nM.

Example 10

[0176] Analysis of Oligonucleotide Inhibition of Fetoprotein Transcription Factor Expression

[0177] Antisense modulation of fetoprotein transcription factor expression can be assayed in a variety of ways known in the art. For example, fetoprotein transcription factor mRNA levels can be quantitated by, e.g., Northern blot analysis, competitive polymerase chain reaction (PCR), or real-time PCR (RT-PCR). Real-time quantitative PCR is presently preferred. RNA analysis can be performed on total cellular RNA or poly(A)+ mRNA. The preferred method of RNA analysis of the present invention is the use of total cellular RNA as described in other examples herein. Methods of RNA isolation are well known in the art. Northern blot analysis is also routine in the art. Real-time quantitative (PCR) can be conveniently accomplished using the commercially available ABI PRISM™ 7600, 7700, or 7900 Sequence Detection System, available from PE-Applied Biosystems, Foster City, Calif. and used according to manufacturer's instructions.

[0178] Protein levels of fetoprotein transcription factor can be quantitated in a variety of ways well known in the art, such as immunoprecipitation, Western blot analysis (immunoblotting), enzyme-linked immunosorbent assay (ELISA) or fluorescence-activated cell sorting (FACS). Antibodies directed to fetoprotein transcription factor can be identified and obtained from a variety of sources, such as the MSRS catalog of antibodies (Aerie Corporation, Birmingham, MI), or can be prepared via conventional monoclonal or polyclonal antibody generation methods well known in the art.

Example 11

[0179] Design of Phenotypic Assays and in vivo Studies for the Use of Fetoprotein Transcription Factor Inhibitors

[0180] Phenotypic Assays

[0181] Once fetoprotein transcription factor inhibitors have been identified by the methods disclosed herein, the compounds are further investigated in one or more phenotypic assays, each having measurable endpoints predictive of efficacy in the treatment of a particular disease state or condition.

[0182] Phenotypic assays, kits and reagents for their use are well known to those skilled in the art and are herein used to investigate the role and/or association of fetoprotein transcription factor in health and disease. Representative phenotypic assays, which can be purchased from any one of several commercial vendors, include those for determining cell viability, cytotoxicity, proliferation or cell survival (Molecular Probes, Eugene, Oreg.; PerkinElmer, Boston, Mass.), protein-based assays including enzymatic assays (Panvera, LLC, Madison, Wis.; BD Biosciences, Franklin Lakes, N.J.; Oncogene Research Products, San Diego, Calif.), cell regulation, signal transduction, inflammation, oxidative processes and apoptosis (Assay Designs Inc., Ann Arbor, Mich.), triglyceride accumulation (Sigma-Aldrich, St. Louis, Mo.), angiogenesis assays, tube formation assays, cytokine and hormone assays and metabolic assays (Chemicon International Inc., Temecula, Calif.; Amersham Biosciences, Piscataway, N.J.).

[0183] In one non-limiting example, cells determined to be appropriate for a particular phenotypic assay (i.e., MCF-7 cells selected for breast cancer studies; adipocytes for obesity studies) are treated with fetoprotein transcription factor inhibitors identified from the in vitro studies as well as control compounds at optimal concentrations which are determined by the methods described above. At the end of the treatment period, treated and untreated cells are analyzed by one or more methods specific for the assay to determine phenotypic outcomes and endpoints.

[0184] Phenotypic endpoints include changes in cell morphology over time or treatment dose as well as changes in levels of cellular components such as proteins, lipids, nucleic acids, hormones, saccharides or metals. Measurements of cellular status which include pH, stage of the cell cycle, intake or excretion of biological indicators by the cell, are also endpoints of interest.

[0185] Analysis of the geneotype of the cell (measurement of the expression of one or more of the genes of the cell) after treatment is also used as an indicator of the efficacy or potency of the fetoprotein transcription factor inhibitors. Hallmark genes, or those genes suspected to be associated with a specific disease state, condition, or phenotype, are measured in both treated and untreated cells.

[0186] In vivo Studies

[0187] The individual subjects of the in vivo studies described herein are warm-blooded vertebrate animals, which includes humans.

[0188] The clinical trial is subjected to rigorous controls to ensure that individuals are not unnecessarily put at risk and that they are fully informed about their role in the study. To account for the psychological effects of receiving treatments, volunteers are randomly given placebo or fetoprotein transcription factor inhibitor. Furthermore, to prevent the doctors from being biased in treatments, they are not informed as to whether the medication they are administering is a fetoprotein transcription factor inhibitor or a placebo. Using this randomization approach, each volunteer has the same chance of being given either the new treatment or the placebo.

[0189] Volunteers receive either the fetoprotein transcription factor inhibitor or placebo for eight week period with biological parameters associated with the indicated disease state or condition being measured at the beginning (baseline measurements before any treatment), end (after the final treatment), and at regular intervals during the study period. Such measurements include the levels of nucleic acid molecules encoding fetoprotein transcription factor or fetoprotein transcription factor protein levels in body fluids, tissues or organs compared to pre-treatment levels. Other measurements include, but are not limited to, indices of the disease state or condition being treated, body weight, blood pressure, serum titers of pharmacologic indicators of disease or toxicity as well as ADME (absorption, distribution, metabolism and excretion) measurements.

[0190] Information recorded for each patient includes age (years), gender, height (cm), family history of disease state or condition (yes/no), motivation rating (some/moderate/great) and number and type of previous treatment regimens for the indicated disease or condition.

[0191] Volunteers taking part in this study are healthy adults (age 18 to 65 years) and roughly an equal number of males and females participate in the study. Volunteers with certain characteristics are equally distributed for placebo and fetoprotein transcription factor inhibitor treatment. In general, the volunteers treated with placebo have little or no response to treatment, whereas the volunteers treated with the fetoprotein transcription factor inhibitor show positive trends in their disease state or condition index at the conclusion of the study.

Example 12

[0192] RNA Isolation

[0193] Poly(A)+ mRNA Isolation

[0194] Poly(A)+ mRNA was isolated according to Miura et al., (Clin. Chem., 1996, 42, 1758-1764). Other methods for poly(A)+ MRNA isolation are routine in the art. Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 60 μL lysis buffer (10 mM Tris-HCl, pH 7.6, 1 mM EDTA, 0.5 M NaCl, 0.5% NP-40, 20 mM vanadyl-ribonucleoside complex) was added to each well, the plate was gently agitated and then incubated at room temperature for five minutes. 55 μL of lysate was transferred to Oligo d(T) coated 96-well plates (AGCT Inc., Irvine Calif.). Plates were incubated for 60 minutes at room temperature, washed 3 times with 200 gL of wash buffer (10 mM Tris-HCl pH 7.6, 1 mM EDTA, 0.3 M NaCl). After the final wash, the plate was blotted on paper towels to remove excess wash buffer and then air-dried for 5 minutes. 60 μL of elution buffer (5 mM Tris-HCl pH 7.6), preheated to 70° C., was added to each well, the plate was incubated on a 90° C. hot plate for 5 minutes, and the eluate was then transferred to a fresh 96-well plate.

[0195] Cells grown on 100 mm or other standard plates may be treated similarly, using appropriate volumes of all solutions.

[0196] Total RNA Isolation

[0197] Total RNA was isolated using an RNEASY 96™ kit and buffers purchased from Qiagen Inc. (Valencia, Calif.) following the manufacturer's recommended procedures. Briefly, for cells grown on 96-well plates, growth medium was removed from the cells and each well was washed with 200 μL cold PBS. 150 μL Buffer RLT was added to each well and the plate vigorously agitated for 20 seconds. 150 μL of 70% ethanol was then added to each well and the contents mixed by pipetting three times up and down. The samples were then transferred to the RNEASY 96™ well plate attached to a QIAVAC™ manifold fitted with a waste collection tray and attached to a vacuum source. Vacuum was applied for 1 minute. 500 μL of Buffer RW1 was added to each well of the RNEASY 96™ plate and incubated for 15 minutes and the vacuum was again applied for 1 minute. An additional 500 μL of Buffer RW1 was added to each well of the RNEASY 96™ plate and the vacuum was applied for 2 minutes. 1 mL of Buffer RPE was then added to each well of the RNEASY 96™ plate and the vacuum applied for a period of 90 seconds. The Buffer RPE wash was then repeated and the vacuum was applied for an additional 3 minutes. The plate was then removed from the QIAVAC™ manifold and blotted dry on paper towels. The plate was then re-attached to the QIAVAC™ manifold fitted with a collection tube rack containing 1.2 mL collection tubes. RNA was then eluted by pipetting 140 μL of RNAse free water into each well, incubating 1 minute, and then applying the vacuum for 3 minutes.

[0198] The repetitive pipetting and elution steps may be automated using a QIAGEN Bio-Robot 9604 (Qiagen, Inc., Valencia Calif.). Essentially, after lysing of the cells on the culture plate, the plate is transferred to the robot deck where the pipetting, DNase treatment and elution steps are carried out.

Example 13

[0199] Real-time Quantitative PCR Analysis of Fetoprotein Transcription Factor mRNA Levels

[0200] Quantitation of fetoprotein transcription factor MRNA levels was accomplished by real-time quantitative PCR using the ABI PRISM™ 7600, 7700, or 7900 Sequence Detection System (PE-Applied Biosystems, Foster City, Calif.) according to manufacturer's instructions. This is a closed-tube, non-gel-based, fluorescence detection system which allows high-throughput quantitation of polymerase chain reaction (PCR) products in real-time. As opposed to standard PCR in which amplification products are quantitated after the PCR is completed, products in real-time quantitative PCR are quantitated as they accumulate. This is accomplished by including in the PCR reaction an oligonucleotide probe that anneals specifically between the forward and reverse PCR primers, and contains two fluorescent dyes. A reporter dye (e.g., FAM or JOE, obtained from either PE-Applied Biosystems, Foster City, Calif., Operon Technologies Inc., Alameda, Calif. or Integrated DNA Technologies Inc., Coralville, Iowa) is attached to the 5′ end of the probe and a quencher dye (e.g., TAMRA, obtained from either PE-Applied Biosystems, Foster City, Calif., Operon Technologies Inc., Alameda, Calif. or Integrated DNA Technologies Inc., Coralville, Iowa) is attached to the 3′ end of the probe. When the probe and dyes are intact, reporter dye emission is quenched by the proximity of the 3′ quencher dye. During amplification, annealing of the probe to the target sequence creates a substrate that can be cleaved by the 5′-exonuclease activity of Taq polymerase. During the extension phase of the PCR amplification cycle, cleavage of the probe by Taq polymerase releases the reporter dye from the remainder of the probe (and hence from the quencher moiety) and a sequence-specific fluorescent signal is generated. With each cycle, additional reporter dye molecules are cleaved from their respective probes, and the fluorescence intensity is monitored at regular intervals by laser optics built into the ABI PRISM™ Sequence Detection System. In each assay, a series of parallel reactions containing serial dilutions of mRNA from untreated control samples generates a standard curve that is used to quantitate the percent inhibition after antisense oligonucleotide treatment of test samples.

[0201] Prior to quantitative PCR analysis, primer-probe sets specific to the target gene being measured are evaluated for their ability to be “multiplexed” with a GAPDH amplification reaction. In multiplexing, both the target gene and the internal standard gene GAPDH are amplified concurrently in a single sample. In this analysis, MRNA isolated from untreated cells is serially diluted. Each dilution is amplified in the presence of primer-probe sets specific for GAPDH only, target gene only (“single-plexing”), or both (multiplexing). Following PCR amplification, standard curves of GAPDH and target mRNA signal as a function of dilution are generated from both the single-plexed and multiplexed samples. If both the slope and correlation coefficient of the GAPDH and target signals generated from the multiplexed samples fall within 10% of their corresponding values generated from the single-plexed samples, the primer-probe set specific for that target is deemed multiplexable. Other methods of PCR are also known in the art.

[0202] PCR reagents were obtained from Invitrogen Corporation, (Carlsbad, Calif.). RT-PCR reactions were carried out by adding 20 μL PCR cocktail (2.5× PCR buffer minus MgCl₂, 6.6 mM MgCl₂, 375 A each of DATP, dCTP, dCTP and dGTP, 375 nM each of forward primer and reverse primer, 125 nM of probe, 4 Units RNAse inhibitor, 1.25 Units PLATINUM® Taq, 5 Units MULV reverse transcriptase, and 2.5× ROX dye) to 96-well plates containing 30 μL total RNA solution (20-200 ng). The RT reaction was carried out by incubation for 30 minutes at 48° C. Following a 10 minute incubation at 95° C. to activate the PLATINUM® Taq, 40 cycles of a two-step PCR protocol were carried out: 95° C. for 15 seconds (denaturation) followed by 60° C. for 1.5 minutes (annealing/extension).

[0203] Gene target quantities obtained by real time RT-PCR are normalized using either the expression level of GAPDH, a gene whose expression is constant, or by quantifying total RNA using RiboGreen™ (Molecular Probes, Inc. Eugene, Oreg.). GAPDH expression is quantified by real time RT-PCR, by being run simultaneously with the target, multiplexing, or separately. Total RNA is quantified using RiboGreen™ RNA quantification reagent (Molecular Probes, Inc. Eugene, Oreg.). Methods of RNA quantification by RiboGreen™ are taught in Jones, L. J., et al, (Analytical Biochemistry, 1998, 265, 368-374).

[0204] In this assay, 170 μL of RiboGreen™ working reagent (RiboGreen reagent diluted 1:350 in 10 mM Tris-HCl , 1 mM EDTA, pH 7.5) is pipetted into a 96-well plate containing 30 μL purified, cellular RNA. The plate is read in a CytoFluor 4000 (PE Applied Biosystems) with excitation at 485 nm and emission at 530 nm.

[0205] Probes and primers to human fetoprotein transcription factor were designed to hybridize to a human fetoprotein transcription factor sequence, using published sequence information (a genomic sequence of human fetoprotein transcription factor represented by the complement of residues 7500-160000 of GenBank accession number AC096633.2, incorporated herein as SEQ ID NO: 4). For human fetoprotein transcription factor the PCR primers were:

[0206] forward primer: TCCTGGTTACTGGGCAACAAG (SEQ ID NO: 5)

[0207] reverse primer: GGAGAGAACGAAGTTTTGCCACTA (SEQ ID NO: 6) and

[0208] the PCR probe was: FAM-CACAAGCCGGAGCCACCCTCAAC-TAMRA (SEQ ID NO: 7) where FAM is the fluorescent dye and TAMRA is the quencher dye. For human GAPDH the PCR primers were:

[0209] forward primer: GAAGGTGAAGGTCGGAGTC(SEQ ID NO:8)

[0210] reverse primer: GAAGATGGTGATGGGATTTC (SEQ ID NO:9) and the PCR probe was: 5′ JOE-CAAGCTTCCCGTTCTCAGCC-TAMRA 3′ (SEQ ID NO: 10) where JOE is the fluorescent reporter dye and TAMRA is the quencher dye.

Example 14

[0211] Northern Blot Analysis of Fetoprotein Transcription Factor MRNA Levels

[0212] Eighteen hours after antisense treatment, cell monolayers were washed twice with cold PBS and lysed in 1 mL RNAZOL™ (TEL-TEST “B” Inc., Friendswood, Tex.). Total RNA was prepared following manufacturer's recommended protocols. Twenty micrograms of total RNA was fractionated by electrophoresis through 1.2% agarose gels containing 1.1% formaldehyde using a MOPS buffer system (AMRESCO, Inc. Solon, Ohio). RNA was transferred from the gel to HYBOND™-N+ nylon membranes (Amersham Pharmacia Biotech, Piscataway, N.J.) by overnight capillary transfer using a Northern/Southern Transfer buffer system (TEL-TEST “B” Inc., Friendswood, Tex.). RNA transfer was confirmed by UV visualization. Membranes were fixed by UV cross-linking using a STRATALINKER™ UV Crosslinker 2400 (Stratagene, Inc, La Jolla, Calif.) and then probed using QUICKHYB™ hybridization solution (Stratagene, La Jolla, Calif.) using manufacturer's recommendations for stringent conditions.

[0213] To detect human fetoprotein transcription factor, a human fetoprotein transcription factor specific probe was prepared by PCR using the forward primer TCCTGGTTACTGGGCAACAAG (SEQ ID NO: 5) and the reverse primer GGAGAGAACGAAGTTTTGCCACTA (SEQ ID NO: 6). To normalize for variations in loading and transfer efficiency membranes were stripped and probed for human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) RNA (Clontech, Palo Alto, Calif.).

[0214] Hybridized membranes were visualized and quantitated using a PHOSPHORIMAGER™ and IMAGEQUANT™ Software V3.3 (Molecular Dynamics, Sunnyvale, Calif.). Data was normalized to GAPDH levels in untreated controls.

Example 15

[0215] Antisense Inhibition of Human Fetoprotein Transcription Factor Expression by Chimeric Phosphorothioate Oligonucleotides Having 2′-MOE Wings and a Deoxy Gap

[0216] In accordance with the present invention, a series of antisense compounds were designed to target different regions of the human fetoprotein transcription factor RNA, using published sequences (a genomic sequence of human fetoprotein transcription factor represented by the complement of residues 7500-160000 of GenBank accession number AC096633.2, incorporated herein as SEQ ID NO: 4; GenBank accession number AB019246.1, incorporated herein as SEQ ID NO: 11, and GenBank accession number AF124248.1, incorporated herein as SEQ ID NO: 15). The compounds are shown in Table 1. “Target site” indicates the first (5′-most) nucleotide number on the particular target sequence to which the compound binds. All compounds in Table 1 are chimeric oligonucleotides (“gapmers”) 20 nucleotides in length, composed of a central “gap” region consisting of ten 2′-deoxynucleotides, which is flanked on both sides (5′ and 3′ directions) by five-nucleotide “wings”. The wings are composed of 2′-methoxyethyl (2′-MOE)nucleotides. The internucleoside (backbone) linkages are phosphorothioate (P═S) throughout the oligonucleotide. All cytidine residues are 5-methlcytidines. The compounds were analyzed for their effect on human fetoprotein transcription factor mRNA levels by quantitative real-time PCR as described in other examples herein. Data are averages from three experiments in which T-24 cells were treated with the oligonucleotides of the present invention. The positive control for each datapoint is identified in the table by sequence ID number. If present, “N.D.” indicates “no data”. TABLE 1 Inhibition of human fetoprotein transcription factor mRNA levels by chimeric phosphorothioate oligonucleotides having 2′-MOE wings and a deoxy gap TARGET CONTROL SEQ ID TARGET SEQ SEQ ID ISIS # REGION NO SITE SEQUENCE % INHIB ID NO NO 148214 Coding 4 14067 tcggtccggaagcccagcac 95 16 1 272226 5′UTR 4 2172 gcttgtcaaatttcgtggcc 42 17 1 272227 Start 4 2248 ttagaagacattcttagtga 27 18 1 Codon 272228 Coding 4 14114 ttgggcagcatgacaaggcg 88 19 1 272229 Coding 4 14119 ccactttgggcagcatgaca 98 20 1 272230 Coding 4 14124 cgtctccactttgggcagca 99 21 1 272231 Coding 4 14129 gcttccgtctccactttggg 84 22 1 272232 Coding 4 14162 ccctgttccccatgcgatcg 89 23 1 272233 Coding 11 316 tgagacacttgcatgttttc 93 24 1 272234 Coding 11 321 taaattgagacacttgcatg 98 25 1 272235 Coding 11 326 cattttaaattgagacactt 89 26 1 272236 Coding 4 18185 ttcaccattttaaattgaga 96 27 1 272237 Coding 4 18190 agtaattcaccattttaaat 56 28 1 272238 Coding 4 18195 ataggagtaattcaccattt 97 29 1 272239 Coding 4 18205 gatcttcatcataggagtaa 87 30 1 272240 Coding 4 18210 ttccagatcttcatcatagg 90 31 1 272241 Coding 4 18215 agctcttccagatcttcatc 93 32 1 272242 Coding 11 580 gcccttacagcttctagctt 88 33 1 272243 Coding 4 22624 tgtctctcttgtacattggc 99 34 1 272244 Coding 4 22676 agcttaagtccattggctcg 97 35 1 272245 Coding 4 22697 atcacctgagacatggcttc 99 36 1 272246 Coding 4 22702 cttggatcacctgagacatg 99 37 1 272247 Coding 4 22772 agaggtaggcctttggaggc 94 38 1 272248 Coding 4 22814 ggacttctgtcatagtctgt 97 39 1 272249 Coding 4 22819 caaagggacttctgtcatag 98 40 1 272250 Coding 4 22847 ggcattgtcatgctaatggg 82 41 1 272251 Coding 4 23027 ttcaaaagttccagtatcag 95 42 1 272252 Coding 4 23032 cacacttcaaaagttccagt 98 43 1 272253 Coding 4 23189 atactactcctggcccactc 98 44 1 272254 Coding 4 23194 agaagatactactcctggcc 98 45 1 272255 Coding 11 1234 ttcatttggtcatcaacctt 91 46 1 272256 Coding 4 85613 gcagcttcatttggtcatca 97 47 1 272257 Coding 11 1347 aatagtccacttgttgccca 99 48 1 272258 Coding 4 148558 atagggcacatccccgttca 88 49 1 272259 Coding 4 148563 ttattatagggcacatcccc 83 50 1 272260 Stop 4 148610 gggttgtaacttatgctctt 64 51 1 Codon 272261 3′UTR 4 148632 gttttgaaagcagagctcct 75 52 1 272262 3′UTR 4 148822 cctttgattcacagtttgca 85 53 1 272263 3′UTR 4 148865 ccattacaatgtcttttata 72 54 1 272264 3′UTR 4 148958 tcttcatagtggagatcagt 77 55 1 272265 3′UTR 4 148965 ctaaatttcttcatagtgga 61 56 1 272266 3′UTR 4 149032 tttaccatggaggaatcctg 76 57 1 272267 3′UTR 11 2334 ctcaaattaggctgttcatg 71 58 1 272268 3′UTR 4 149248 aatagaatttcctattagct 62 59 1 272269 3′UTR 4 149315 tcttaacatcatgaacacga 88 60 1 272270 3′UTR 4 149431 tagcagaaataaggtctaag 82 61 1 272271 3′UTR 4 149451 aagccacatttcagcaacag 89 62 1 272272 3′UTR 4 149456 tgccaaagccacatttcagc 90 63 1 272273 3′UTR 4 149511 gactgatgtatactaacaag 85 64 1 272274 3′UTR 4 149633 tgcatagattaacatgcgtc 83 65 1 272275 3′UTR 4 149668 gagtcaatacatcacctcat 92 66 1 272276 3′UTR 4 149830 acagcagactttggtctatg 86 67 1 272277 3′UTR 4 149877 tagtcatttgaagaatttgc 86 68 1 272278 3′UTR 4 149894 gttaataatactgataatag 41 69 1 272279 3′UTR 4 149966 tgatccacatctgcacagct 84 70 1 272280 3′UTR 4 150024 tgtaaacactatatcttatt 66 71 1 272281 3′UTR 4 150040 ctcaggacctaaagaatgta 83 72 1 272282 3′UTR 4 150095 acattaaggaaattaccgct 79 73 1 272283 3′UTR 4 150185 agtctaaatgagattcccgt 70 74 1 272284 Intron: 4 13103 caatttcctcgatctgaggg 19 75 1 exon junction 272285 Intron: 4 13172 cgggtcttacagctagtcag 39 76 1 exon junction 272286 Intron: 4 23218 ggtggcataccttaagttct 97 77 1 exon junction 272287 Intron 4 24119 tctccccgttacagcaaaag 99 78 1 272288 Intron: 4 85721 ctacactcacttgttgccca 98 79 1 exon junction 272289 Intron 4 103555 ggcagaggtcctgactgggc 90 80 1 272290 Intron 4 105079 caggttttgctgtttcaaaa 98 81 1 272291 Intron 4 144965 gttcacaaggacctaaaagc 72 82 1 272292 5′UTR 4 2054 tttccctggactctgtactt 0 83 1 272293 3′UTR 4 150602 ccaccttgttgagtttactt 74 84 1 272294 3′UTR 4 150343 gcatcataattgtctacagt 77 85 1 272295 3′UTR 4 150452 tgaactaagttccactaatt 74 86 1 272296 3′UTR 4 150466 ctcttctatgtccctgaact 75 87 1 272297 Exon: 15 20 tttcctcgatcaataggtgt 35 88 1 exon junction 272298 Exon 4 13115 cagccagagcggcaatttcc 34 89 1 272299 Exon: 15 92 agcccagcacagctagtcag 70 90 1 exon junction

[0217] As shown in Table 1, SEQ ID NOs 16, 19, 20, 21, 22, 23, 24, 25, 26, 27, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 70, 71, 72, 73, 74, 77, 78, 79, 80, 81, 82, 84, 85, 86, 87 and 90 demonstrated at least 60% inhibition of human fetoprotein transcription factor expression in this assay and are therefore preferred. More preferred are SEQ ID NOS: 21, 36 and 78. The target regions to which these preferred sequences are complementary are herein referred to as “preferred target segments” and are therefore preferred for targeting by compounds of the present invention. These preferred target segments are shown in Table 2. The sequences represent the reverse complement of the preferred antisense compounds shown in Table 1. “Target site” indicates the first (5′-most) nucleotide number on the particular target nucleic acid to which the oligonucleotide binds. Also shown in Table 2 is the species in which each of the preferred target segments was found. TABLE 2 Sequence and position of preferred target segments identified in fetoprotein transcription factor. TARGET SEQ ID TARGET REV COMP SEQ ID SITEID NO SITE SEQUENCE OF SEQ ID ACTIVE IN NO 63635 4 14067 gtgctgggcttccggaccga 16 H. sapiens 91 188446 4 14114 cgccttgtcatgctgcccaa 19 H. sapiens 92 188447 4 14119 tgtcatgctgcccaaagtgg 20 H. sapiens 93 188448 4 14124 tgctgcccaaagtggagacg 21 H. sapiens 94 188449 4 14129 cccaaagtggagacggaagc 22 H. sapiens 95 188450 4 14162 cgatcgcatggggaacaggg 23 H. sapiens 96 188451 11 316 gaaaacatgcaagtgtctca 24 H. sapiens 97 188452 11 321 catgcaagtgtctcaattta 25 H. sapiens 98 188453 11 326 aagtgtctcaatttaaaatg 26 H. sapiens 99 188454 4 18185 tctcaatttaaaatggtgaa 27 H. sapiens 100 188456 4 18195 aaatggtgaattactcctat 29 H. sapiens 101 188457 4 18205 ttactcctatgatgaagatc 30 H. sapiens 102 188458 4 18210 cctatgatgaagatctggaa 31 H. sapiens 103 188459 4 18215 gatgaagatctggaagagct 32 H. sapiens 104 188460 11 580 aagctagaagctgtaagggc 33 H. sapiens 105 188461 4 22624 gccaatgtacaagagagaca 34 H. sapiens 106 188462 4 22676 cgagccaatggacttaagct 35 H. sapiens 107 188463 4 22697 gaagccatgtctcaggtgat 36 H. sapiens 108 188464 4 22702 catgtctcaggtgatccaag 37 H. sapiens 109 188465 4 22772 gcctccaaaggcctacctct 38 H. sapiens 110 188466 4 22814 acagactatgacagaagtcc 39 H. sapiens 111 188467 4 22819 ctatgacagaagtccctttg 40 H. sapiens 112 188468 4 22847 cccattagcatgacaatgcc 41 H. sapiens 113 188469 4 23027 ctgatactggaacttttgaa 42 H. sapiens 114 188470 4 23032 actggaacttttgaagtgtg 43 H. sapiens 115 188471 4 23189 gagtgggccaggagtagtat 44 H. sapiens 116 188472 4 23194 ggccaggagtagtatcttct 45 H. sapiens 117 188473 11 1234 aaggttgatgaccaaatgaa 46 H. sapiens 118 188474 4 85613 tgatgaccaaatgaagctgc 47 H. sapiens 119 188475 11 1347 tgggcaacaagtggactatt 48 H. sapiens 120 188476 4 148558 tgaacggggatgtgccctat 49 H. sapiens 121 188477 4 148563 ggggatgtgccctataataa 50 H. sapiens 122 188478 4 148610 aagagcataagttacaaccc 51 H. sapiens 123 188479 4 148632 aggagctctgctttcaaaac 52 H. sapiens 124 188480 4 148822 tgcaaactgtgaatcaaagg 53 H. sapiens 125 188481 4 148865 tataaaagacattgtaatgg 54 H. sapiens 126 188482 4 148958 actgatctccactatgaaga 55 H. sapiens 127 188483 4 148965 tccactatgaagaaatttag 56 H. sapiens 128 188484 4 149032 caggattcctccatggtaaa 57 H. sapiens 129 188485 11 2334 catgaacagcctaatttgag 58 H. sapiens 130 188486 4 149248 agctaataggaaattctatt 59 H. sapiens 131 188487 4 149315 tcgtgttcatgatgttaaga 60 H. sapiens 132 188488 4 149431 cttagaccttatttctgcta 61 H. sapiens 133 188489 4 149451 ctgttgctgaaatgtggctt 62 H. sapiens 134 188490 4 149456 gctgaaatgtggctttggca 63 H. sapiens 135 188491 4 149511 cttgttagtatacatcagtc 64 H. sapiens 136 188492 4 149633 gacgcatgttaatctatgca 65 H. sapiens 137 188493 4 149668 atgaggtgatgtattgactc 66 H. sapiens 138 138494 4 149830 catagaccaaagtctgctgt 67 H. sapiens 139 188495 4 149877 gcaaattcttcaaatgacta 68 H. sapiens 140 188497 4 149966 agctgtgcagatgtggatca 70 H. sapiens 141 188498 4 150024 aataagatatagtgtttaca 71 H. sapiens 142 188499 4 150040 tacattctttaggtcctgag 72 H. sapiens 143 188500 4 150095 agcggtaatttccttaatgt 73 H. sapiens 144 188501 4 150185 acgggaatctcatttagact 74 H. sapiens 145 188504 4 23218 agaacttaaggtatgccacc 77 H. sapiens 146 188505 4 24119 cttttgctgtaacggggaga 78 H. sapiens 147 188506 4 85721 tgggcaacaagtgagtgtag 79 H. sapiens 148 188507 4 103555 gcccagtcaggacctctgcc 80 H. sapiens 149 188508 4 105079 ttttgaaacagcaaaacctg 81 H. sapiens 150 188509 4 144965 gcttttaggtccttgtgaac 82 H. sapiens 151 188511 4 150602 aagtaaactcaacaaggtgg 84 H. sapiens 152 188512 4 150343 actgtagacaattatgatgc 85 H. sapiens 153 188513 4 150452 aattagtggaacttagttca 86 H. sapiens 154 188514 4 150466 agttcagggacatagaagag 87 H. sapiens 155 188517 15 92 ctgactagctgtgctgggct 90 H. sapiens 156

[0218] As these “preferred target segments” have been found by experimentation to be open to, and accessible for, hybridization with the antisense compounds of the present invention, one of skill in the art will recognize or be able to ascertain, using no more than routine experimentation, further embodiments of the invention that encompass other compounds that specifically hybridize to these preferred target segments and consequently inhibit the expression of fetoprotein transcription factor.

[0219] According to the present invention, antisense compounds include antisense oligomeric compounds, antisense oligonucleotides, ribozymes, external guide sequence (EGS) oligonucleotides, alternate splicers, primers, probes, and other short oligomeric compounds which hybridize to at least a portion of the target nucleic acid.

Example 16

[0220] Western Blot Analysis of Fetoprotein Transcription Factor Protein Levels

[0221] Western blot analysis (immunoblot analysis) is carried out using standard methods. Cells are harvested 16-20 h after oligonucleotide treatment, washed once with PBS, suspended in Laemmli buffer (100 ul/well), boiled for 5 minutes and loaded on a 16% SDS-PAGE gel. Gels are run for 1.5 hours at 150 V, and transferred to membrane for western blotting. Appropriate primary antibody directed to fetoprotein transcription factor is used, with a radiolabeled or fluorescently labeled secondary antibody directed against the primary antibody species. Bands are visualized using a PHOSPHORIMAGER™ (Molecular Dynamics, Sunnyvale Calif.).

0 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 156 <210> SEQ ID NO 1 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 1 tccgtcatcg ctcctcaggg 20 <210> SEQ ID NO 2 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 2 gtgcgcgcga gcccgaaatc 20 <210> SEQ ID NO 3 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 3 atgcattctg cccccaagga 20 <210> SEQ ID NO 4 <211> LENGTH: 152501 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <400> SEQUENCE: 4 agttcgagac cagcctggcc aacatggcaa aaccccatct ctactaaaaa tacaaaaatt 60 agccgggcat ggtggcacgt acctgtaatc ccagctacta ggggggctga ggcaggagga 120 ttgcttgaac ctgggaggcg gaggttgcag tgagccaaga ttgtaccact gcagtccagc 180 ctgggcaatg gagcaagact ctgtcattaa aaaaaaaaaa aaaaaaagga ctggcctggg 240 tttacaggta gctcacacct gtaatctgag cacttgggga ggctgaggca ggaggactgc 300 ttgaacccag gagaccaacc tgggcaatac agcaacacac tgtctctaca aaacatttaa 360 aaaattagct gggtgtggtg gtacacatct gtagtcctag ttactcagga ggctgaggca 420 ggaggattgc ttaagtccat gagtctgagg ttgcagtgag ctatgactgt gccactccat 480 tccagcctgg gtgacagagt gagatcccat ctctaaataa attaatagac cataaattct 540 gtaatgtgaa tctttagaca aagactgcta aatctatcat ctgatatatg aagttttatt 600 acaacaaatg tttatatatt gagttaaaaa ttatctgtac ccatacacac aacctgcatt 660 tacttaattt aaaaggagtg tcaatattaa aattgaggat tttggccagg tgcggtggct 720 cacgcctata attccagcac tttgggaggc cgggtagatc atttgaggtc acaagtttga 780 gaccagcctg gccaacacgg tgaaaccccg tcttgactaa aaatgcaaaa attagccggg 840 catggtggtg tgcccctgta atcccagcta ctggggaggc tgaggcggga gaattgcttg 900 aacccgggag acagaagctg cagtgagccg agatcgtgcc actgcactcc agcctgggca 960 acagagcgag aacccatctc aaaaaaaaaa aattgttatt ttgttgttat tgttgttttt 1020 gaagacagag tctcactctg ttgcccaggc tggagtgcgg tggcatgatc ttggattgtg 1080 ttcttccagg gttgcagaga gaagtgcaac agcgtctcat tgcaacctct gcctcccagg 1140 ttcaagcaat tctcccgcct cagcctccca agtagctggg attacaggag tgcaccatca 1200 cacccagcta atttttgcat ttttagtaga gatggaggtt tcaccatgtt ggccaggctg 1260 gtctcgaact cctgacctca ggtgatccgc ctgccttggc ttcccaaagt gctgggatta 1320 caggtgtgag ccaccatgcc cagcctaaga ataataactt tataactatg aaaaatgtgt 1380 tacatattca ccattttgcc agcattaatc tcaaagcata agttttacct tttggggata 1440 aagagataga ttgtgtttta gccatatgac caatgtagaa acaagctaag gttaactcct 1500 catctaatga ataggcccga taaaaaagtt ggttgaccac aacatgaata aataaataac 1560 cataagcttg gaaatgctac ctgtagtatt tcagagtgtc gatcacattt gtagtcatca 1620 cttaaagaat taatgtctgc caatgttatc atctaaaatg tatttacaga ggtcagaaga 1680 gctatgtctg tcctcctcta tgcaaagagg tgatgacatc aaggggtatg tcacaagcca 1740 aagtttagtt agcctaagtt agttagctgg tttgcagttt ttatccacta agtctgatct 1800 tctgacccct cagttttaca actttccact ctctgtgctg catagcacct ctccacttct 1860 gagttaatca tttctttgcc attatctggc aagaattctt atctcttttg ctgtcacttt 1920 ataacagggt cctcttatca acctgcatag agtcatgtga tgagtcaaag cctatcaaaa 1980 gtttccattc ttctgattag aaaccatcat gaaactggat acatggttta cagcaggtca 2040 ctaatgttgg aaaaagtaca gagtccaggg aaagacttgc ttgtaacttt atgaattctg 2100 gatttttttt tttcctttgc tttttcttaa ctttcactaa gggttactgt agtctgatgt 2160 gtccttccca aggccacgaa atttgacaag ctgcactttt cttttgctca atgatttctg 2220 ctttaagcca aagaactgcc tataatttca ctaagaatgt cttctaattc agatactggg 2280 gatttacaag agtctttaaa gcacggactt acacctattg gtaagtagga gtttctctat 2340 tgatcatcta tttattctgc tactacatac atataattta atcttgttga tggattttgc 2400 attttaagtc atggcttttc ctattatgtt tattaaaagc acacaataag cctatgtata 2460 tatatcacac atttatcttt cttgcagttc aaaaaaagca aatggatatt tcaacatatg 2520 aatattattc attatatcta gtgtttactg gtgtcattct aataccctaa tcagccagaa 2580 aatataattt atactttatc aatttcaact ttaatatttt ctgataattt ttaatcagaa 2640 ataataagct aaaatttgaa caatttgaaa caagttaatc atattgagtg atcattgatc 2700 aaactttaac agatagctgt caagtatttg ttacttttca acccacacaa aagtatggtg 2760 tcttattctc tgcttatacc gtaaaaaatt ttcattttat tttcctgggg aatgaaagtc 2820 atgcccccac ctccaaaaaa aaaaaaaaaa aaccaaaaaa actagaccat cattagtaaa 2880 ggatttgaag agctactgtt tctcgcaaca attagtatat tttgttttta caaacagaaa 2940 taagtaaata aagctactat tcatttaaaa aatagagtta caaacttatg aattttatag 3000 caagactaca ttcaattaat tctaaaagta aaggactgaa gggaagtgat tcccagtgat 3060 ctgtaattat ttgtctgttg gaagtcaggc ccttctgcct ttccccagtt tttgaaggac 3120 ctgtgccttt tctggcagca tttgcctagg ctttcagact ggaatttccc tccgaatttg 3180 caggggcctg tcatgagctc tctgagtctc agctccatta taacaagaaa gaaaatcaag 3240 gcttgagttt ttcctctttt ttccttccta gtcagctgac tccacagaat gcagtggagt 3300 cacagattgc tttttttatg ggccaactac accctaaagt atatcacttg aggaaatgtt 3360 taccaaaaat gttctatact tacgaaaaag aaaacatggg gaaggtaagc agggtgtaac 3420 acacaatcaa ttgttctgca gataacacag aaaatacagg cacaagaaag atgagagagc 3480 agcacacaac catttcgcat ctttttcgtc gggcagaacc gccgcggtgc gcaggcaagg 3540 agtccttccc ggcagctccg cgcagctccg gttccgcgtc cggggccgca gctagagcgc 3600 gctcgggccg gagacgcgga ctgcgcgcgc acgggggacg cgcgctcggg ggctcgcgcc 3660 cgcgcgggcg gtcttgggct cctgctgcgc gcagccccag ctggccgctg ccaaaataga 3720 gttgagctgg gtcgggagac cacgcacgcc gatccctcac agtctccccc acaccccatg 3780 ggtgaattaa agagggtaag gtaggggaaa gagacgctgt tgcacttttc tctgcaaccc 3840 tggaagaact gtgtttccag ctaccgcacg cgcaactcac atcgcaaggg accgaggcgg 3900 tacactctga gcgtaaacag agaacacctg cagctctgga atcggtccca ccgcagaggg 3960 ctgggaaccg gaggactgtc ggtccagccc ataaggggct gctggggact aaacctcaag 4020 aaaagtaccg aagaaggctc tcccctggcc tcagcgagac taccccaaca tcctaaacct 4080 gtgcaggcac ttccgggcgc cggattccgg gataacaaaa ttccagtcaa tttgccggta 4140 aaagagacct ctttcaggat cttgttcgca gccacccgcc ccttcccaac ccaagcacat 4200 cccctccgcc tcctggtatt gcagccccgc aggtggttgt gaggtgtccg cacctgcaac 4260 atcttagtga ccctgaggcg gctgtggcac cgggagacaa tctgtttacc tcgtagcctc 4320 cacgagggtg ctaacggtcg ttcccagggt gaatggctgg acggagccat ccaaagggct 4380 gagggagagg aacagagggc ggtgaggagc cttcggactg aactattgga ttgaagggcc 4440 tgacccgatt cctgagggag agatgcccct tgaatgggtc tttctgattg cccagggtag 4500 ccccactggg aagaacccac gggtgcagct gtagagagtg tctgagggtc tcgagggtag 4560 ctttcagatg gcaaattgca agttgggctg tgttgagtgg ttcacaaaac cgagcccggt 4620 gtatgtagac atcagtcagg gtttacaatt ctatatttaa ttcagttgtg ttgtactagg 4680 aaatgagcct ccttttgttt aaaaagctgt ctccatggtt tttaactagg ggctacatct 4740 tgtatgcaca ctgatggtta catgaaagtt ttgtatagat gtctgtgctt gtatagaaaa 4800 gcagaattaa gataaagttg ttccttctgc ctacctgcaa gataatcatt cattgtagtg 4860 taaaagcagc acactcaggt tataactaga ttgttccctt aaagttaact aactctggga 4920 cactggccag actcttggtt tctggtcttg gtttacttct ttctcccaag tgggatgatt 4980 ctattgaata atatgcagta ctaactttag aagcttttta tacttaccta tatcaagaaa 5040 agagccatat ctgtgtggta ggaaatgtta tacataaaac aaatatttat tgaccactcc 5100 cacagtgccc aatattatgc tttgattcat attaaatttc cataattctt caaattaact 5160 gcatttgcag aatattttat gcactcagta taatattgca tattatccac agaaggttat 5220 gtctgcatac ttaggggtac atgatacaca gtgcaaacac tgtattgagt ctgtaatgtg 5280 agtcttgcta tctggtcccc tgaacactct gagtctgatt ttatttcagt gataacctcc 5340 agcaagctct gtgctcataa ggatctctga aagtagacgt ttcatcagcg gaaagtgtga 5400 tagccattat gtcaccctaa cctccagcga gctttattta gaatgccagc cacacaagcc 5460 catgttctga ttctcatagt tggggcttag gctgccagtt tcttctatga agctaaactc 5520 tagagcctcc cttctttcca tgcccgagtc catctccaaa acagtgcttc tcagattcct 5580 cttttctggc ctggatccac aggtagtgac cagagttaac agagttcttg ggccaggcac 5640 agtgtctcaa actggtaatc ccaatacttt gggagactga ggatggagga tcacttgggc 5700 ccaggagatc cagaccagcc taggcaacat agtgagaccc agtctctaca aaaaataaaa 5760 aaataaataa ttagctgggt gtgggtgtgg tggcatgtgc ctgtagtcct agtgactagg 5820 gcttgggggt tgaggtagga agatcacttg agccagggag gttgaggatg ctgtgattgt 5880 gccattgaac tccagcctgg gcaacaaagt gagaccctat ctcaaaaaaa caaaacaaaa 5940 caaaacaaaa caaaaaaagg atttcttttt ctttaacacc tttttttttt tttttttttt 6000 ttttgaggca gagtttcact cttgttgccc aagctggagt gcaatggcat gatcttggct 6060 cactgcagcc tcagccttct gggttcaaga gattctcctg cttcagcctc ccaggcagct 6120 gggattacag gtgcacgcca ccacgcctgg ctaatttttt gtatttttag tagaaatggg 6180 gtttcaccat gttagccagg ctggtcccga aatcctgacc tcaggtgatc cacccacctc 6240 agcctcccaa agtgctggga ttacaaatgt gagccaccac acctggcatc tttaacacct 6300 cttctaacaa accaagagag atttatagag gaagggagaa cagaggcttg ttaatgcttc 6360 tctcctttac ttgacccctc taccagacac aatgtctagg attatcttgg attcagcctt 6420 gagcataagt tgagctagag aagggcacat tgtcagactt ccacctacag gcccaaccca 6480 atccccaccc ccagggatgc actaggcagg caagacaact tcactccgca gctctagagt 6540 ctaccttagg atagaactag ttctttgagt tgcacttcct cacgcttcac cttattggaa 6600 cagacttctt ggaaaaatcc agttggcttc aaggaacttc aggagggcat tgtgctctgg 6660 ggaggccctg gggaagtgtt gaaatgtgac caatatgatc ttgagagatc aagcttgaga 6720 aaaccatgtg aactggaact gaccaggcaa gctgataaag gttgtctctt ctttagtctt 6780 ttgggaagct gttatgtatg tttttgtgtg gttgataagt aagaaaagat atttggagtg 6840 taacttttaa acaccaaata acctgaatgc agatgaccat gagcacttat atgagcagtt 6900 ttatctggtg ataatgtaat tgtccccaag gactttgtca agccctgcaa gacaatcaag 6960 ttagcaagca catcccactg gaaggtgatc ctagaatggt tagtgattcc ctttttactt 7020 tccttacaga atgatgagtt tgagtgaagc taaggggaaa gacaaagggg aactgatata 7080 tatatatata tccagcgtaa tatatttctt tcctggcact gtctcattta actataaagt 7140 ttactttgtt aacccaattt tactgattaa aaaatggaat cagaggtcaa gcaatttact 7200 cagcttgtca agagaatgaa ctgtaaatag aacccaagaa atattctgaa atacatactc 7260 tttctccaaa gtggtaacca cttgttcttg ttgatataaa ggaattatga tttaatacaa 7320 tgttggtcta tgcagacttt cctccaatgg acatttcgag cttaagaaac atatttgtaa 7380 gtggcttttt aatcttcatt tccattccac ggtagaaacc atatttggat ccttctagaa 7440 ttcagaaggg tggcacaggg agtggtgtat ggaaagcaga gtggaaatca catctgggag 7500 gactgaggtc tgagtggggt gggacaaagg cacttctggt cccctactct ggagtttcct 7560 ggaaaggatc tctggagttt ggatgaagtt tagcttgtga atttgtggtg tatggtaaca 7620 actcgcaggg ttaccaacag atggtgagaa ggaactgaga ggaaattcag agcatgtact 7680 tgttatagag tcagtgagta tgaggagggc agggaaatca ctcaaactga gtgactgaat 7740 tagatagcat aaacaaacat actgttgtac catgagagga ggggataggg aaagacaatt 7800 taggtgtcaa ttaaaaaaaa aagcactttt gacaaaccca gctgtgcctc ttgcagtgag 7860 atatgctagt cccacaccca tgctagcatt tttcacggta agtgctggat tccttgctca 7920 gggtttggat gcctgcagcc tctgcttccc ggccttctgc aagctccacc tgctccagcg 7980 gcctctacag gaatggaaag aaaattggtc ggaatccact gctgggtcct ggaatcaact 8040 tcccagtttc cagacaagaa actctggaga aaacaagtga atctctctca agccttggca 8100 cacactgtac accatctcgt aatcgcgaaa gttatcacca tgttggaaaa gcccacgccc 8160 ttctaattgt gcaacctctg taactgccca gaccataaca ctttccctag ttccacgccc 8220 catgcttgag tgtgacggta ccactgttaa gtcttgcctt tccaagctcc cactttcttt 8280 gctgaccaag tgagacccaa attgctggac tccgcacctc tgcggtcccg gcactctttg 8340 accttaagaa tcagaagctc aggcaggggc ttttctgaag gaagaagttt ggttggatcc 8400 atcccctcgc tgcaaaagcc gaggaattct gaagcaatgc aggatgtttc cccttccatc 8460 aagaagtttc cagtatcgcc ggatacattt aaatggcagc ctagaataat ctcgtgctaa 8520 ggattttgtt cctgacccag gttgaagcgg aggagagggt gtaaaggatg caactgcaag 8580 tgttcagcta gtttcacaag gtgctttgtg gcctactagc gccgggatcg tcgttctgtt 8640 ggccccgagg ctggacagaa ttgattccaa tggatggagt cccaatagtt ttgaactgga 8700 actggctcaa atttccattt caattacaga gaggaagaga tagattagac cacctacccg 8760 agattatttc ccctgcccca ctcctttctt aagaccggat ctccctgtta cattcttcta 8820 agggcaccga ctataccctg gcggggcact ccaggacccc tgggttggga caacgtgctg 8880 taaagaaaat aagtgaaaag gttcttcagt gaactctttt tatacaaaga gccgtagatt 8940 ccgatatcca ggccaaactc tccaaaaagc cctcctttcc tctggggcaa gggtgggagg 9000 ttgcccgggg gggtgggtgg ggggtaggtt ggattaccca gataattgct tcggctttcg 9060 ttttcctccg cgataaaaac cgcgccacgc cagatcgaga tactctcata gtgattgtga 9120 atcaatcgcc atcctgctct aggggctgat gttgatgtct taagtagtta ttcacacgtg 9180 cagcagaaag gctttttttt tttttttttt tttttttttt tttaaacaag gcacgactgc 9240 tcacctattc aggtttgctt ttttaaagct tcgatcaaca cgacgctccc tggtaattcc 9300 tatggctgta ctgaaattta acccgtctgt ttctaataca aagcgctcgg gatgagggcg 9360 ggtggagcct acgggcgtgg gcgggtagcc cagccctctg agccagggaa tgaaactgga 9420 gttctggcta aacttttcag agaaaggcaa aagcagcttc tgatgggttt ttcggctggg 9480 aggggcggaa aaattaggca gacccggagc tcccgtaggc tgaaaaactt gctcctcttc 9540 cccctcgggc tatcctggcc tagtaatgga gatctgaaaa aaatctagac ttctttcggg 9600 gtctaaaagg tagatatgtg ggacgaaaaa agtaattgtc ctggtttctt aaaaagcacc 9660 aaaaagtggg aatggaagag aagacgggag aaattgtttc gaaggaggaa ggtattgcaa 9720 gttttgtgca agtttgggtg ggtcatctac ccaggcgcgc ggggaaagat gtgtctgcca 9780 caccttttgc gagcccagga aacttgaacc gctcctgaaa atcctgatat tttttcccgc 9840 tgcagcccgc acgggtcaag cgcgcggggg ctgaccaaca ctttccaggt caggtcgagt 9900 tgattgctcc cagctcacgc tccgaaatgc ggtgctgaac cacgggaagg agggggtggg 9960 gaggaaggca ggcagttgca tcctcgcgag tggggagtgc gaggcctcct cagctccagc 10020 cagctgggtg aatggggcgc gcacggcccc gtaacgccga gcgtggataa aatatgctag 10080 gactgcgctt ctccggctca tcaaggctgc gggagcctcc ccgagccatc atccttcgta 10140 attgcaaccg tcaatcaaca ctttaagaca aagtcagaac cgggaagggc gagccctgga 10200 gacctgtctc gtcggaaaga aggaggtgga ggggaggtgg gggaaaagga gagaagtttg 10260 ccagaagttg gcagagggag tgcaaagaaa ttgagaacgc gcaaggtagt tgagcagagc 10320 tgtcccccgg tctcaccaca gactcccagg cctcccgggt tctagtctct ggtctccgcc 10380 accagttaca attcccgcag cggtaagtac ggggtgggtt cctaagtgtg cttacactaa 10440 gaggtacagt ggcagttgct aagatgtccc cggcggagga tgagatgcgt ctgtccaccc 10500 gcggtaggtg tatttatggg tcagtgcaga ccaccgctgg cgccggcgtt tagaccacac 10560 agacccggtt ccacctactt acatctcaac tgctttccct tcccgcagcc acttggctgt 10620 cttcatattg tggcctcggg aacccagaac cattctcaaa taacccatct tagacaccgc 10680 aaactcgggt tcctcctccc acagcttcct ttcggagagg gctttctggg ggacgcccag 10740 acccgtccaa ggtcactgag ctagcgggtc cccggcttca acaggggtcc cttgcccagc 10800 agaattgaag ggtcaaagga ccagagtgag tgctcagagg gaggagggag ttctgaggga 10860 gaagaaaggg tgcacttgga gggcagtaat gagcttgacg ctggaagcct ggtgccgccg 10920 cccctgcctc tgcctcttgg atggagaccc agctgcttcc ttaaatccct tgcagagcta 10980 cctgaggaag gtttgtgtgc cctcgggtct ctggcaagaa tcaattccag tggaagattc 11040 cttgccttgt ccactgctgg cggggatctt gacatccttc caggggatct gaaatagggc 11100 tgcccccagg gagcgtttcc catcgtcgag ttaaaggcct ggagcgccga gggcttaggc 11160 ttctgagcta ggagttccct tggttcttag gaaaggtcgt tttctctcgc tcgagacttt 11220 ctgctctttc agtccccctc catttcgctg ctacgcttag gttttggcct ggactagact 11280 ttcaaagcaa aggaaagggc ttccctccgt gatacaagct cctgcgttaa ttttttaaag 11340 catggatttt taaaacccag tccccagcca ccgttccctc ccgcacccct cccattttgt 11400 gaggattttt ctttcctgga aagtccacct gtggagagat aaatgagtgc cagctggcct 11460 tttgccacca ccactctcca tctttcgggg atgtggtggg agggtagact ggcatggacc 11520 aagaagtcgc tagtgtggcc taagcaagtc ccttctggcc ctggcagctg gcgttatgag 11580 catggtcaca aagcttgtct cactaggtca gcctcagcct caggttcagc ctcaagccaa 11640 ggcagggttt cttgatacac tacaatttca aggtcctgtc agaccctctt tcaacttctt 11700 tcaactctcc taacttcccc cggcttcacc aagcagaggt gaaatcacca ccacacacta 11760 ggggttggag gtttcctctt aggaccaagc gtttggagtc ctgcatcctt gccatgctag 11820 ggtctgggaa aggtgctgta tcataagtgc acccataaat tcttcgcatt gctgtgggag 11880 gaggttcttc ttaattaagg ctttgaaata aactgatttt caaagttcac gagcaaagca 11940 gggcaaccac tgcagtgagc cctgaaactg actccctttc tttattttct tagttctcag 12000 tgatacttaa aacaactagg aatactgaaa tgtagtgaca gtgatacttg atactatcac 12060 aaaaattgga gcttttggca acttcagccc acttctccat acaaactaat ggacaggcct 12120 tcataagttt aaatgtttcc acgaaacctg aagttgctac taaagctgaa gtctaaataa 12180 ctttgatcct gaatatatat tgaagagcaa aatgacaaat caattaagag tcagtagtac 12240 ctgaattgcc aggtgtgggt gggtgatgaa caacccattt tatgtacatt atgcactgca 12300 aagattggaa taatttccaa gtcaccaaat accggattgg gcagtttcaa tgtgtaatct 12360 ctataccatt caaatagaat aaacttagat cttttgagat tcaaattcac ccccttgtgg 12420 gtggactctg ataattactt cgttgcacag cagattctaa atatgaggca tttcgcatgc 12480 agtcaggagg ctggaaagaa tgtttttcat cttgttggga ggagatctga aaactttgaa 12540 gatgcggctg ggctggtggt cgaagagctt gcgtaacaga tggttcttta aaacattttt 12600 taaatgctgg gcctcggcct caagtggatg gtcccatcag acaacagaat gaaaaagtac 12660 agcctggact gatccttgta ttccgtgtgg aaacacaggt cactaaaact ggaaagtctg 12720 tcgcttagat gatcttgggc tccagtcgag ggtcttttaa aagtgaacga agggactagg 12780 gagcagactg gggaaagagg agtcgctgcc ccttcctcta attctatgag tgagctcttg 12840 gcttgtggcc cgcctctcat tgagctgacc ctcggcccct tcagggcgcc ggggcccacg 12900 tgtcgcctct tcagggtctc agtgccctgg ggagttgaag ctggaggacc cttgaccgca 12960 gaccaactct gcatgtaaga acggtcagct aaattttctc ctttcaatgg tttaagtggg 13020 tgtttaactc ccttcatctc ctcatccgac acactagcaa gggcacacgc ccacccgcgc 13080 ccccatccct tcttcttgct tcccctcaga tcgaggaaat tgccgctctg gctgcttctc 13140 cttcgccgcc acgctcagac agaggtcgct tctgactagc tgtaagaccc ggctgcattt 13200 acatcccccc gccccgggcc agggtggggt gggagggggt gaggcggggt gaagaggttg 13260 gggcaggccg ggggactgga gcctgagcct catccttatt ggctggcggc tagtgtccga 13320 cctgagtccg gaacccgcgt ccgcattcac tgtcttcacc cctcaatcca gccttccccc 13380 aacccctggc cctacttacc tccttctccc cctcgtcttc ccccctgtcc ttcccagcac 13440 cgtcaccctc ggggctggga agggccgttc tcggtcccgc gcggggagtg gaccaggcag 13500 gagagggagg ttggaacttc acaactccac acttgcgata gtgagcaaga gagaggcaga 13560 gagagatagg gggaaggggc ggagaggagg ggagagagaa gggaggcgag agaaagagga 13620 gagagacccc tgccgatcct gagccagagg gcggtggagg gaggggaagg agtcgcccga 13680 gccgtccggg agcagtggca gcggcacagc cggggcggca atagcagccc cgcggtcgcc 13740 tccgctgccc gccgggagct cggcggttca cggctccgcg ccccgggcag ctgcgtcctc 13800 gccaccgccg ccgcctgcgc ccttgcggag ccgaaccaga gggccgggac gctgtcttcc 13860 tcgcctcctt ttttaaccct gacctcctcc tcgcagcttg ggggcggctc cggagctgcg 13920 agaccggaca gggctcagag gtcctgcccg gcagccccga ggaggcggag gcacgctccg 13980 gcgaggcgag agggttgggt tagcaggcat cccggtcgcc ccttccttct tttcgccgga 14040 gttgaatctg tgctgcccgt gtccaggtgc tgggcttccg gaccgacacg gatcccccat 14100 ccccgcccgc ggtcgccttg tcatgctgcc caaagtggag acggaagccc tgggactggc 14160 tcgatcgcat ggggaacagg gccagatgcc ggaaaacatg caaggtaagg aggcgccgcg 14220 cggcgctccg gctcccgctg cttccccacc cccgggctcg ccctgcaggc ttcagcctcc 14280 cgccccgcgc gggcgcggga gtagccccgc tgggcgctcg cagccgcggg agtcaagccc 14340 cctccccagg tgcaggcata aaagtttatg gctcttgaac aatgcggggc agaggttttt 14400 ccaagcaacg tctaattggc cgcttctaat taaggaaaga gaggcttcca gctctatggc 14460 aacccaagca gggcagcttc aggctaaagg tactttagaa taataagatc attctaagaa 14520 atggaatgtc tcactggaca cccgaacagg ttctctgtca ttggaattgg tgtgtactgt 14580 acttcaacca gtactcttgt gtggagggag gcgacccagt ctaggaaagt caactacaga 14640 aagaggtgac ctccgaaagg attgtcttag cgctattaga atacatgtga ccacaccaaa 14700 agcccaggcg gacacccgca gccagctcgg atttggacaa ttcaacattg ctggcagaac 14760 tgaagggaac aagttacccc aaccccatcc cctgtacgcg tagtgctgag tgagttgggg 14820 gtgggaggac agcggttcgt ttattgcccc cttttaaaat ctgagatctg aaaatatgga 14880 ggtcccattc gttttcccag ctcttgattg ccaacaaaaa aacaaatccc gctggctaca 14940 ttttctcctc attccaaaat agcaacccta tggcttgtat taagcccttc agaagtttat 15000 ctcatttgct ctgggccagg gagggaacaa tgctaggaaa agtcaccggt gctcttccat 15060 cctcgcccct tccagggtgc aggatgtgcg ggccggcggg cctgtgatcc cggaacgctt 15120 cctgccatcc ccttgcgcga acttgaaagg actgggaggt gttgagagca gagttcaggg 15180 ctggtgcact ctgcggtgct gagtgggcgg cgcgcccggg cgctcaggcc gggggacctg 15240 tagtcgccct accgcggagg ggaaaatacg tagctggagg gcgtgcgccg tgcgggttgt 15300 gatccgttac cccatcggtc atcctggggt ctccccaagc ctctaggtag ggctgtgaga 15360 gtcccctaga gctgaagccc cggaggctga cctgtgggtc tggctgctat gggaacccgg 15420 ttggtccaaa gaagcctttc ttccgggcac ctggaattcc agtttagtgt ggggcatcgg 15480 ggaagtggcg ctggggggct gggttggggg acctcagccg gcagctccgg agagggccta 15540 cccttggggt cgctgggtga ggccggcacg attcttggct ccaaaaggaa agtttctgct 15600 tcttgttctg gcgcgagaag ccaaagactt attttgagag cggagagaga aatgttattg 15660 gtaacgtttt ctttggaaag ttcgagaggg gtcttctgga cacactacct agtgccccca 15720 aaccagagaa gtagtttttc tttggtgcct gggctcagaa gtcgccactc actcagccca 15780 tggttcgaaa tcagcatggg aagcgccggg gcaaggcttc gtcggagact agaggcctgc 15840 ctgtcgggag gagcccctgg gggatgggga ccccattctc ctgcttgctc tggttcccac 15900 ctgggacgcc tccgtaggag cccagaaaga cgatccacta catggtcccg ggacagagca 15960 gcgcgcccaa ctttgaggga actttgtgcg cctctctgag gccctagctt tccaaggcac 16020 cgccgtccgt tcttctttcc ctagaccgaa actggggaag agtgtgggcg cttctttgcc 16080 ccgatgagtt cgcctcccca aacgcctact tcggctgcac cagagcatct gggaaactct 16140 gaaaggtgcc caggcctcac acagcagcgt ctccctactc agcctctgtc tttgggtttt 16200 ttcaagagag tctctacctc atgcctcggt ctttcttcga tgtcgggtcc ccgaggtagg 16260 cacggagtcc ctctgaaagc agttgcctat ctgtgcccct ttggtgtaaa gttagagttt 16320 actttgttgg gggaagggga ggtagaaaag atcacagttg ggaaagtgcg cttttcgcct 16380 tgttcctaaa acatgcctca agactgtcat cgcgattgtt aggagagcta tcaacgtcta 16440 ggggctataa aggaatttct gaaccctcgg cccttcccaa acccccaggt tcctaaaacc 16500 ctagtggggg tctcttgggg ctgggattca ggctggcacc gctgggagga cctcgcctag 16560 catcccttta ttaatatttc acgaaggcag gctcctgcct tctctggagc ctcttttctc 16620 ggaatgttcc caaactctgg ctaactcact cccctgtgag ccatcctagg gctctgtggc 16680 ccgggaagag acgcgtcaac tccgcgggtc tgcgcgcagt ccttagccgc aaagtgctgc 16740 aagtgacccc cctgacggcc ctttccgacc gaagagctcg ggaaccaaag agaaaaaaaa 16800 taactttatt ttcaaaagaa caagtcatca ctgcggcgat actgtggcgg aggactttgg 16860 cgatggggtg ggggctattt ctctttcctt tttggtaaac aaatcagagg aaacttctgc 16920 ccggccgtgg ctttccatcc cccacctgcc ccaccccctg caaacgccac tgattaactt 16980 aaaacaaact cggctgcgtg tttgtgcgcc gttgggtagc aggaggtaga gcctaggcga 17040 gagcctggtg cgcccacggg tttcgccgaa gagtgcccgg gggagtgcgg gcagggtccc 17100 ggctgcgcag acctgcgggt gcccgcccac ccgcgccccg cgctcccata cttgacctgt 17160 gtggatgtgg agtctccggg aaataccgga tcaggcactt cctggggtct cctggtcact 17220 gcccttcctg tgcatagttt gtcatctttt tagctgcgaa gacgccttcg tgggtctgcg 17280 tccggagcaa ggcggttacc cgatcccggc agtgagccgc gccgcgcgtc gtggcggcct 17340 gatttctgtt taactttaat agggcgatct cgaggtgttt atattttgct atgatgatcg 17400 gaaacatgtg aggttcatta cagggcttca atactttgaa accaaaaccc ttctgtgtgt 17460 cttttactct tctggtattt ttccccgtac gggcgtcctc tattttcttt ttccttcttt 17520 ttattttcac agattttcaa acgtaaggag atgaaagtat ccagaataga aaagtactgt 17580 caatacggaa ctgaatgttt cgattatcta acagatctga aagttgggag cctcaggctg 17640 tttagttaaa gtgggctgct gctgagaagc gggtttctgg ggcttcagtt tctctgtcgg 17700 acagagtttg caaattggtg ctgctgtccc tgtaagcaag gtgcacttgc agcaaaccac 17760 ttcaagaggg agggaataaa gcctgcgctt gtttctctac cttaggcgaa ggtgacattt 17820 tggaatttaa cttcataggg atttaaaaga aattctaaac tgtcacctta tgcaattcat 17880 gtctctattt gttgctttgt ggagttatga gacttgtgtt taaaagcggt cagtttaaaa 17940 tgttaacaaa agaagttgga attgtttgtg gcacatggaa ttatatgagg tccatgctta 18000 ttgatgacaa aagatgtttt acttgtaaaa atagttcagt aagaccttgc taaaaattgt 18060 ttttatttta tattttacca tgtgatattt gcccagcaat caccaaaatg ctttttgttg 18120 caggattaac acctacatgt aaattaattg aatatgtgta tacatttctc tttttgtttc 18180 agtgtctcaa tttaaaatgg tgaattactc ctatgatgaa gatctggaag agctttgtcc 18240 cgtgtgtgga gataaagtgt ctgggtacca ttatgggctc ctcacctgtg aaagctgcaa 18300 ggtttgctca cacattgcta cctgaaaaat ataatgtcca acaccaaaat aaaccagtgg 18360 attacttctt ttaagctaaa tttaggctcc ttttttaaag actcaactaa aaatgaggga 18420 gaaagagaga gtcttaggga gatgattctt agaagtgtgt gtctgattta gttcaaaagg 18480 caaagaaatt tatgctgttt agaaaacttt gccagtctca tggttctaaa atactttatt 18540 gtagtaaagt gatatagctg tagaaagact tccatttcta acagtcctaa atattgattt 18600 tgcttgactt atatatattt aaagcatcgt tgttcttgaa agggaatatg acaaactatt 18660 tcccaaatac attttaactt cagagtattt ctgtgctata agtctaaaca ttctttatcc 18720 acagacataa aagcctaaat tcccaactgt gtgatttcat cttgatttat tccaaaataa 18780 ttttaaggat tttttgaaat ttatatcata aagaccaaga aatcagattt tagtttttaa 18840 tataataatt tttataaata tatgacctat ttaagtgcat ggattttaat atgtaaaata 18900 tgctatattg ttaccaaaaa tataaattat actttaagaa tttatctcag gactttttaa 18960 tacattccca gtaaattcaa tattcactat ttttcaaagt tttttttgtt tgtttgtttt 19020 tgtttttaag tggaaaactc agtacaatta cttaaaccac caccaggaaa atccctccat 19080 tctctataac aaagtaagaa tgtttctctt tgtggcaagt gggttaaata tgaatactat 19140 cctggtaaat ctcatattat aaagctacac attttatttt tgattaattc ttttatataa 19200 aatataagga aagctcatac cctgtgtgct acaattcagc tatctgtgat acatgctttt 19260 tccttccatt agttttgcct ttttaagaac agttcccata cttgaatgta ttccagtgga 19320 attatgagca ttttcccatt ttactcttta aatccttttg cttttaacta tccagtgttg 19380 acatttgtta aaaaaaaaaa aaaatctgag gtgttttgct attcagtttt ttccactggc 19440 attttgcaat ggtttatcac tgaaattata tcagactact taaaaacaat gccaggactt 19500 catgagtacc tctatcagga acatgtggga taataggaaa atagattaaa aaaaaattta 19560 tctatataga gtgtattttt tctgactgtt gggataaaat ggtgggtagc caaatctccc 19620 caggatttga cgtaattctt caagaataaa actgatgcca gaaaaatctc caccatggcc 19680 tggcacagtt tgggaaggtt gatgttgctg aaatgtaaaa taaaccacag aaccacataa 19740 gggctcaaat agtgcaatga gaggatttac tggtgatttt cttaaaatga aacaatggaa 19800 aagacgggtg ttagatttat aatacgtctc actattttct ctgtcttata gggatttttt 19860 aagcgaacag tccaaaataa taaaaggtac acatgtatag aaaaccagaa ctgccaaatt 19920 gacaaaacac agagaaagcg ttgtccttac tgtcgttttc aaaaatgtct aagtgttgga 19980 atgaagctag aaggtaagat tcttctaaag actactgcct attaaaactc tccaaggaca 20040 tgaactgtaa aacaacattg tacttatagc atggtaacat tattttccca gcattttaac 20100 actaccgaca atactgtaag atctttctat gtttcatctg cagaatagtc tgagtctcat 20160 ttaatcatgg tgaaatctac taggaaaaaa atttaaaata ttagttgtct ttcccctgcc 20220 cacccccttt tttttagtct ggggagcaga tgcattagac acaaaaaagg gaaaaagatc 20280 aggttatgaa aataagacta aagcaatcca actgaaaaca agaataattt gtaaaactat 20340 taaaagtaaa atattctttg agtttttaaa tcaagatacc cttggaaaag tttgatttca 20400 attcttttta aaagaggtgt gcttgtcaca agtgttaact actaatttca tgattcttaa 20460 gagttaaagc ctttaatggt gaaaaggagt ttctcatgta ggatattatc tttgatagtg 20520 tagaaatgta tttttttaaa agataatgac tgaggctgca aaataaaaaa ttgagaatca 20580 ggaaacatga aaaataacga actattaaat cattagcaaa ggtctgaaaa gaacaagaaa 20640 gtggctcctg aaaagccaca cttgaacttt gttgaaagag cagaccctat actacaatgt 20700 acagattggc aggcagtaaa gttaatatgt gactgctgta aataatttgt agttcatgga 20760 ctactatggt atgttgctgc tttctagcct ctgacctgct tgctttccat ggattaaata 20820 tactgcaaat aaagcaataa cagggataca tatcaccgat ggtgctagat acaagagtgc 20880 attttatttg atcaatgagg cacaggctat ttttatttgg aacttttctg ttatatggaa 20940 ctcatacttg atagaaatac taaaaaaaaa aatcatataa atctgctgaa tagctaacac 21000 gcttcttccg aacagaggta gccactttgg ttattatgag gactgttaat gtcagtatca 21060 tttttaagag atcatgaaag gaaataattg atgcttatta attttcttat taccaatcac 21120 tattatttcc caaatagcaa aatattgtgg tagatgctta ctacatacag taagagactc 21180 agaagataag taaatgttgt gattttgcat gatgtcattt aattcctttt caacaaaaat 21240 aataaggctg catttcttta ccttaaataa ttaaactttc ttttttttaa gttaagcttt 21300 cacaattgta aatcacttgt ggtacatgct catgcttcct taggagtgat atgaaacaac 21360 tgaatattca ataaattatc atccagatga aaaactcttt ataatcttgt gcaatattct 21420 gtatacttag aatttacaat aaatttttaa tgtgatacta atccaagata aaaagctcaa 21480 aaacttaacc tccagcaagt tcaatatgtc acaagctatc agaggtctct agtttctgtc 21540 taattgccat tggccactat ggacttagag ggaactgcta actaacttat tagtcatggc 21600 cgcagactcc acacaccact gtcgcagaag actctcttga cagcttctga aatgaatttg 21660 ttttaattat gtccaattct acttaaatta aaagcagtaa ctggtggtca tctgatgtgg 21720 gctcatcaag tccaggtgaa catgattttc caagaacatg tccccacccc ttttgttatt 21780 gcaacaaggt ggccaaaatg gctttcaggg aggaaggtat cttgtgggaa agtattcaca 21840 atttaatcca aaattgggta actcagttcc acacccctgc aaaagaaaac cccaaagcag 21900 tttgggtttc cataaggaac tggcataata aaagcatata ctcttagtag aacgactgat 21960 actctttctt agcaatgtga aatatttctt ttcttttttt tgagacaggg gtttcactct 22020 tgttgcccag gctggagtgc agtggtgtga tcttggctca ctgcaacctc cacttcccgg 22080 gttcaagcga ttctcctgtc tcagcctcct gaatagctgg gattacaggc acccaccact 22140 acgcctggct aattttttgt atctttagta gagatggggt ttcatcatgt tggccaggct 22200 ggtcttgaac tcctgacctc aggtgatcca cccgccttgg cctcccaaag tgcagggatt 22260 acaggtgtga gccaccgcac cacgcctatg tgaaatattt ctatgtctaa caaaaattat 22320 gaactctcct ccatccacaa aagggttaat atgtccctat gtggccaaag tatttttttg 22380 atgacgacac acacttggag gaaggaattc ataaataaag aggacatggt tttttgggaa 22440 atctttgtgg gctattgtaa cgaaaacaac cacacacata ccacttcttg tcgatttaca 22500 tttctaaata tctgaagaat gctaataatt tgcaccttat ttataccttt ccttccttcc 22560 ccccacccca cccccaacag ctgtaagggc cgaccgaatg cgtggaggaa ggaataagtt 22620 tgggccaatg tacaagagag acagggccct gaagcaacag aaaaaagccc tcatccgagc 22680 caatggactt aagctagaag ccatgtctca ggtgatccaa gctatgccct ctgacctgac 22740 catttcctct gcaattcaaa acatccactc tgcctccaaa ggcctacctc tgaaccatgc 22800 tgccttgcct cctacagact atgacagaag tccctttgta acatccccca ttagcatgac 22860 aatgccccct cacggcagcc tgcaaggtta ccaaacatat ggccactttc ctagccgggc 22920 catcaagtct gagtacccag acccctatac cagctcaccc gagtccataa tgggctattc 22980 atatatggat agttaccaga cgagctctcc agcaagcatc ccacatctga tactggaact 23040 tttgaagtgt gagccagatg agcctcaagt ccaggctaaa atcatggcct atttgcagca 23100 agagcaggct aaccgaagca agcacgaaaa gctgagcacc tttgggctta tgtgcaaaat 23160 ggcagatcaa actctcttct ccattgtcga gtgggccagg agtagtatct tcttcagaga 23220 acttaaggta tgccaccagc tattacaact tacagcaccc cttttaagag agacctaact 23280 atgttcctaa ttaatacatt cttggtgctg aaaatatgtg ttccttaatt ttctactttg 23340 tatgatttac agagtagacg taattttatt accttgactt caggactgtg gcagcttaaa 23400 tttatggggc tttgattttg tgtagctctt agtttggggg ggctggcatt taacataaag 23460 tataggaaac tcgggctttt ttttctaaat agtagaatat ctgtattcct tttaattcag 23520 atggtttgtg gcttaaaaca tttcaagtca atgtgaaata gcgcctagta aactattttt 23580 cttgaaaatt accatgtaaa gagctatatt ataatggtgt catcttgaag gtttcttttg 23640 aaggaaaaaa tgccaacatt tagtagtgtt tagactctaa ggaatgaaaa tgataccact 23700 ggttagtagt atcaagtagg tatttactac tgtttgcctt gacattaggt tggtaaagcc 23760 tttgttttcg tagcagattc caataggatg tttactgtca ttggatgggg aatgggcaaa 23820 tggtgagtgc tagtttactt ggtttgggtt gtagttctca taatctatgt cttgttgatt 23880 ttagtggact ggtacattgt aaacatagta cttgtttgta tagggatcta tgtttaaatt 23940 aataattatt ttatttcctg aaacttaagt ctgaatgaat gtgagaaagt tatttagaag 24000 tttggaatct aagaggggct accaaaacac atttggtagt cagtggtttc attcctattt 24060 taaaagtgag tcttgaattt gatttccaag tatattttgt cacaaaatca atttcttcct 24120 tttgctgtaa cggggagaga tgtggctgct aaatatctgt gacttgtgat tacctaggac 24180 aggagattga ttgtaaaatt tctgagagaa ggaaaatgca aagccgactt ttaattttaa 24240 gagttactgt taaaaatcgt ctgtgtaagt agatggtctg gggaatgtgg aagccacatg 24300 caaatggaaa ataatgcttt catagcagtc tacattaagc actgttcttt gtacatggaa 24360 gcaaaaaagt tacctgaaca gacctaaata agttgataaa attccatcag cacgctgtta 24420 agactgtgga cacatccagc tctttatttc cacgtccttt attgctacgc ttaaaaatgg 24480 ctgaaggata tctcaggctg caaagggcaa gcagaatgca ctgcgttagc acaattaggc 24540 cagatatttt ccgagtatgt gttagggttt gtaaccactc tatgataatc agaacatttt 24600 tcatgaaaaa acaaaccatg caaacacttt cctgatattc ttacattcaa aactgtgtcc 24660 ttaatcaaac aggtaaagta tttgaaaatg aaaattaaaa tgataatttt agatactgtc 24720 gaaaggttag gtaatgtaaa aatgaggaaa acacagactt tttacaatca aatgaactgc 24780 ttaataatta tgtcttcata ggcaggttgt tagattctct gagccttggt ttttctcatg 24840 tgtaacttgt atatgtggtg tttgtggagg agtattggga gcacagatgt aactacttat 24900 attgaggagg ttttcaaagg aaaatgagaa tatgcagata aagcacccag taccgggagt 24960 ctggcatata ctacatactc agtaaagtgt ggtgctgttt taaattgata ttactggggc 25020 cgggtgcagt ggctcatgcc tgtaatccca gcactttggg aggccaaggc gggcggatca 25080 cctgaggtca ggagtacgag accagcctga ccaatatgga gaaaccccgt ctctactaaa 25140 aatacaaaaa attagccggg cttggtggca catgcctgta atcccagctt ctagggaggc 25200 tgagacagga gaattgcttg aacctgggag gcggaggttg cggtgagccg agatcttgcc 25260 attgcactcg agcctgggtg acaagagcga aactccatct caaaaataaa taaataaata 25320 aattgatgtt atcactgttg ttttatgaaa aatgtgcaga atctacataa tttttatatt 25380 taggatcaaa acaatgcaat tatagtctct tagtttaaca ttggcaaaaa ctattacatg 25440 tgttatagag tagtatgatt ttgttataat taacagttat taatcagtac taattaagga 25500 cctaaaattg gccaaggggt aagttgggta taaggtaaaa acaacgttga ataaaacaac 25560 atgtttcctc tcagagttta taataagaca gtttcataaa taattatttt aaaaaataaa 25620 gacagccgca gagaataaaa atatatttta caaatcaaca aggaaagaaa taatgcatat 25680 tattttcatg taaaaaagga aacatgaagt aaatacagct agcggctgta aggcattaag 25740 aaggctggga aaactttttc cactattcct ctcttttccc tcctctgtgg ataaatttta 25800 cagtgacttc tttatatagc atgaggttaa atatttggct aaaacataaa tatctttgag 25860 aatggggcat ataaaagcat ttttcaatca attacggtgt tgtttaatgc atttatcagt 25920 ctttcataga atacgaaaaa aggaaaaggg aaaaaagtac aaacgtgagg gtcgtctaca 25980 aggggtggga gatgttccca gaagagaaag ataattttga cccacttcac agtttgcctt 26040 gggcttactt tgaccaggag tgattcaagt attttttggt gaacaaagag tagaattcag 26100 aaaaacttaa ggatagtttc agtagagagt tgggaggtga ctattgacat ttggaagaat 26160 tccttttcct ttcgtttata aatttacttt gtcagaaagc aaaccaactc atttgaagcc 26220 aggattgaga catctctagg gctgtggctt tcaatttttt taatcatgac ccacagtagg 26280 aaatgtattt tatggcagga catagtgtac caaacacatc acacgggcgc acacacacag 26340 agatgcacaa acatacaaac acatacacac aactaaacca aagtttcacc agatagtaca 26400 taacctacaa gccacgcact ctgatatttt ctatctattc tactttagtc taatttattt 26460 catgttttta aaaaaattct ggtcacgact cactaaattg atttcacggc ccattaatga 26520 ggcatgacct gcaattcagg aaaacttgct gctctagagg aggttttatc ggccatccat 26580 tggcgttgcc tacctgctac aattaaggat aataactccg gaaaaaggtc tcttcctcct 26640 ggcgtggcct ataagacatc tttgaaaccc acagcctgag tccccaccct atctttctgt 26700 aaaggttgta attttaaaat atcatttggg aagataaatg ctctttttta ttcaatttga 26760 ttttaattat ttttgtagag acaggggtct cactctgctg cccaggctag tctcaaactc 26820 ctaggctcaa gcaatcctcc tgccttggcc tcctgaagtg ctgggattac agacaggagc 26880 cattgtgcct gttttattca ttaaatatct gtccttttcc ttggtaactt cacagcaaat 26940 tacctatcaa gtgatatact tattggacag attttttata cctctaaaac ccaaagatga 27000 aaaatcacat atttgctcct aattaggcaa ttttgaaatg acctctttct cactctcttt 27060 ttttttttga gacggagtct tgctttgtcg cccaggttgg agtgcagtgg tgcgatcttg 27120 gctcattgca agctccgcct cttgggttca cgccattctc ctgcctcagc ctcctgagta 27180 gctgggacta caggtgcctg ccaccacgcc ggctaatttt ttgtattttt agtagagacg 27240 gtgtttcacc gtgttagcca ggatggtctt gatctcctga ccttgcgatc cgcccgcctt 27300 ggcctcccaa agttctggga ttataggcat gagccaccgc acccggccta cctcttgctc 27360 actctctcag gacaaattac actctctacc acataggaaa aaaagagaat ttcatttgtt 27420 tactagttaa gggaacagaa gggccaggaa atttggtagg ttgttttgtt tttctataca 27480 tctacaaggt gcaaaaaaag gtattctggt tttcattcaa aagattggaa tgaaaaagaa 27540 gaagttacaa ctccccaact ctcatagaaa ccgtggaatt tcagagctgg aagatgaaag 27600 ggaaaagggc tagaggacac atataagcga gctgctttgt ttttttaaca cacttgtaaa 27660 ggacaattct ggtcttcatc caaaataatg gcttgagaaa gatgaaatta atactctgaa 27720 acttgtagct tttgcaacaa cagatgtgca tcaaaagata ctcattgcct agaaatcaca 27780 aggtttttca gagctagaag agatcactga gatcatttga ccctacctct ttttacatat 27840 gaagaaactg aggcagaagg gaatgtaatc tgcccaagat tatccagcta ctgaatggca 27900 gaactgggac tggtagattc aggttcaaag aagcagtcct cttgtacgca ttccctcatc 27960 ccccccagca tgcacacgca cacacacaca cacacacaca cacacacaca cacacaaaga 28020 ggcagtgtaa tctttgactc caaagaaaac agtcctttgc cagtgaagct aaagcaaatc 28080 tctaggttat cagaagccca tcactaccat ccaattacca aatcactaat aatcagtgag 28140 acagattttc cctgagtcca gatgaccccg tgggagtgaa tgagtcactt taaaaagcta 28200 caataattct ttcaggccac tggggtatca ttcagtacag tggattcagc acttctgggc 28260 cttgagtttc tgaagcattc tctagtgccc taccctctgc ggatagttta ctctccaggt 28320 gaatctggtt cagtgacggc atatgggctg tgctctgccg ttaaagcggc caaacacgat 28380 tatatcctgt gctctactag aagctgggca tgttcagtat gggtttcttg ttacgtatgc 28440 ttgtcgagat agcagaaaaa gaatgcaggg agctcacttt ggcagcatat acaataaaat 28500 tggaaagata cagagattag catgaccccc tgcacaaaga tgacacaggc attcatgaaa 28560 ctgtccataa aaaagagaac acaggatggt aaccgggtga taggtgagcc actaataaaa 28620 ttttctgatc tttaaaccaa atctgttgag tgacctatgc tcttgactgt ttccttgtgt 28680 ttttagaaat taagagctaa ttcgagactt ttgtattctg ctgaaagagc tgtccttgtg 28740 agtcaagaag attggctttt tttttcagtt attttttttt tcacctgtgt cttgaatatc 28800 tcacaaacac aagagcagtg agaaaataat tcccactttg ttaaacaact aatgaatctg 28860 gaggatctat ttgatcttct aatgagacca gatgtcttaa gagaattctg ggaatggata 28920 tataagaact tcccctcggt gaatgattct gatacatgta cgtattaaaa aaaatctaaa 28980 ttaatcctga ctgaaactcc caactagcat ttctgtggaa aataggtctc agagactcag 29040 ggagtttgtg ccaaaggaat ttagccatgc tgaagttggt ttttaagtat agctttatct 29100 aaagcgaggg cacaagggga ggagcaaacc ttcttttttc tctagccaat tatggaagct 29160 atctgagcag cattatttat ctatttttaa cattctagat cctttttcct aaatcacagt 29220 tacctttccc aatgcaggcc tataatctca gactttattg aatctgcccc aattttaagc 29280 tatattcttt agtaaattta cttagtccta cttttttttt tttaagacag ggtctctctc 29340 tgttgcccag gctggagtgc agtggcatga tcatagctca ctgcagcctt gaccttgtgg 29400 cctcaagcca tcttcccact ttagcttccc aaatagctgg gaccacaggc gcatgcaacc 29460 acgctagcta attttttatt ttttgtggag atgggatctt gcgacgttgc ccaggctggt 29520 ctggaactcc tgggttcaag cagtcctcct accttggcct cccaaagtgc tggaattaag 29580 gcataaccca ctgtgcctgg cagccctact tttttttttt tgtgacggag tttcactctt 29640 gttgcccagg ctggagtgca atggtgcaat ctcagctcac tgcaacctcc acctcccagg 29700 ttcaagtgat tctcctgcct cagcctcccg agtagctggg attatagcgc ctgccaccac 29760 gcctggttta tttttgtatg ttttagtaga gatggggttt ctccatgttg gtcaggctgg 29820 tctcaaactc ctgacctcag gtgatccact agcctcggca tcccaaagtt tacaggcgtg 29880 aaccactgtg cccagccagc cctacttttc tatgggagag aaagagaaac tgagagagag 29940 gatcctgctc ggtgtctacc acatttactt gccatatggc tgttctttgc cttctcctga 30000 gagttggggt caggaatcat gggtccaaca cgagcactcc tcattgccat gtgatgtcac 30060 agagcaatag ccactttact tacctttgtt ttcacttctc tggatgcaaa gtagctaatc 30120 tgggaagcac aaggatgaca caaagaaaat aaacattaaa gtttgttttc cagtcaaatt 30180 tttcaatgaa tgaaaatttt ccaatcaaaa tttgatctca aggcacatta agccatctat 30240 tgccagttct catactcatc acaaagttgc cagaatgaaa taaatcgaac ctgcataggt 30300 ttacaaggaa atgataaaac tggtttttct tccgctgaag gtagatatga aagtgttctg 30360 tctttgtgaa tttggagaga atgttggaat cagcaggttt gattcatggt ctctaaggtc 30420 tcttcaggtg ttaagcatct gcttttatat ctttttccaa gcagacctga aacagaaggc 30480 tttggtgtgg ctgatagtgt tggatgagaa tttatgttat ttcagccttt cttgcttaca 30540 tacgtatatt gcatgtgtct attgtagact cagaaagcca ttatctttct tcttgctttc 30600 ttctgagctt tcttcttgct cacaattcac tgaaagaatc agctcttctc agtcaatgcc 30660 tgtttgtgct atggccaact cactgtgggg cagtggaaca tgcccactta ctgtggggat 30720 gtgtattgtt ctttactggg atatcttgaa agtacaccag tcacctcaaa actcccatgc 30780 attagttact tctactaagg taaaatttac tctccctaaa atttactgtt tttaatgtac 30840 aaatgataaa acagctcttt cacactttaa aattctcttg tgtccctttg taataaactc 30900 ctctccccac cccagtccct gccaatcctg atctgttttt gtccttagag ttttttttgt 30960 tacttttaaa aagaagtaaa tttgctttat tcgttgagta tacatttaca aactgcaaac 31020 tcagtttaag ctccctgaaa cttatggttt cagcgtagtt gagcactaat agtttccatg 31080 gaaacatatc ctccatgggg cgctgggata tttggtaaga gagtagtgat gatcataact 31140 tcacactggg tctgcttgtt cacatgtctt atgagcgtcc tgttcgtatt aacctgtatg 31200 ttatctactg gaaccatggg gagaacatga gaatagcgag gcacacccaa gaaatccatg 31260 tttaactagc ttggccatcg tcaggtgtct gaatctgaac agtgagagta ggaccacact 31320 gctaccgcat acctgactgc ctcattctgt gtccctcctg ttcgatatag tctggttttg 31380 caaactgagg cttaagcctc ggcagccaag agcaagccct tgttcctgtt ctgatgagga 31440 tgtactgaat tattttgtat tcagtttcct acgatgacct tctctaatta cacaaaagaa 31500 aacataatga atttacatat ctttgggtca atttatgaaa aaccattctt ttcagtaata 31560 caagtccttt aagacctgtt ggaaaatggt acagacgtga gcattttcct tgctctgctc 31620 taggtcatat ggtaaaggag aagagaagta acttttcttg ggtacccact aagcacctac 31680 tctagtgcta ggtgctttca ggccattttc tagtttgatc tttaggacag tccagtgatg 31740 agagcacagt gtatggtcat ttggtcagag tgggagtaaa agaccatcgc tctcgtataa 31800 catgttctct gtggaggata cgtccgtcag tcataatgac tcatagagat gtcaagttaa 31860 ttgattcgta aaagtttgct aaatcaattt tttttctttt tttttgagac agggtctcac 31920 tctgtcgccc agtctggagt gcagtggcac gatcttggct catggcaacc tccacctcct 31980 gcattcaagt gattcgcctg cctcagcctc ccgagtagct gggattacag gcgtgcacca 32040 caacacccat ctaatttttg tatttttagt agagatggga ttttgccatg ttggccaggc 32100 tggtctcaaa actcctgacc tcagggtgat ctgcctgcct cggcctccca aagtgctggg 32160 attatgggca tgagccactg cgcctggccg taattgtgct tttttttcct tttttctttt 32220 tttgagatgg agttacactc ttgttgcctg ggctggggtg caatggcaca gtctcggctc 32280 actgcaacct ccacctcctg ggttccagca attctcctgc ctcagcctcc cgagtagctg 32340 ggattacagg catgcgccac catgcctagc taattttcgt attattagta gaaacaaggt 32400 ttcaccatgt cagccaggct ggtctcaaac tcctgacctc agatgatcca cccgccttgg 32460 cctcccaaag tgctgggatt acagatgtga gccaccacgc tcagccaaat tgtactttca 32520 gtaaagtact ttactgttta caaagaactt ccatatacat ttttttggtc ctggtctctg 32580 tctttcattt tgggagcatg gatgtaactg gcctttcatc aatggttcag tagtgttgtt 32640 ttttaaagcc tacaacagaa ccatctccta tgaattgact atcacctgtc taaatgccct 32700 gtttacagca tgttgtacct gcaagagcag gatatttaaa gtactttata attgataatt 32760 gccattatca atatgctcac ctctttacca tattccaaca ggtcttaaag gacttgtatt 32820 attttttacc gaagagagtg gtttttcgta agtttacccg aagatacata catttattat 32880 gttggttttt tgtttttttt tgtttttgag acagagtcgc actctgttgc ccgggctgga 32940 atgcagtgtc gcaatctcag ctcactgcag cctccgcctt cccggttcaa gcgattctcc 33000 tccgtcaacc tcccgagtag ctgagatcag gcacacgcca ccatgccctg ctaatttttg 33060 tatttttagt agaggcgggg tttcaccacg ttggccaggc tggtctcaaa ctcttgacct 33120 caggtgatcc acctgcctcg gcctcccaaa gtgctgggat tacaagcatg aaccaccgcg 33180 ctgggctggg ttttgttttt tgtttttgtt tttttttttc atattagagg aggcccagac 33240 aggtgcggtg gctcatgcct gtgatcccag cactttagga ggccgaggtg ggaggatcac 33300 ctgaggtcag gagttcgaga ccagcctggc caacatggtg aaaccccttc tctacaaaaa 33360 ttatgaaaat tagcccggcg tggtggcact tgcctataat cccagctact tgggaggctg 33420 aggtaggaga atcacttgac ctcaggaggc ggaggttgca gtaagccaag atcgcactac 33480 tgcactccag cctgggcggc agagtgagac tttgtcttaa aaataataat aataataatt 33540 agaggagacc atcgtaggaa actgaagaca aaataattca gtatgtcccc atcagaacag 33600 gaacagggtc ttgttggttg cagagacttc agcctcattt tgcaaaacca ggctatatat 33660 aattggaggg gcacagaatg aggcagtcag gtatgcatta gcagtgaggt cctccccagc 33720 ttgtgaatac ctgggtaggc ttaccttatc tcccaacctc ccagtgctcg gcactggttc 33780 ctactgaaca atcggtagaa gcaattttgt cagcttgtct gcctagaagt agccacatgc 33840 ttgtttgctg agaataatta gggtccctgc ttattccagt acttatgctt ttccagcagg 33900 cacacagatt gctcacagat cttatggaaa ggctgccagt gttacttcct cagtgttggg 33960 gaggtagagc ccactaagcc tgagccccct gttccctgtc tgcacactgt catacaaagt 34020 cacagaataa gttaaacaca tacacacatg cacacaaaca cacacagaaa acatgactca 34080 tatgtgacat ccctcaacac acttttgaag gactttgccc tctgaaccta tatggtaaaa 34140 tagatctttt ttattttcca ggataaataa agaatgattt tgctctgacc tattcttctg 34200 cagcttggga agtagatcat acaaatcttt gagagttcaa catccatttg cagaatggct 34260 ccatggaaat tggccattta aactattctt cacgttaaag acattaagct ctaacccaag 34320 aaaaccaccc acagccaaga acaacaaaaa tgacataaac cacgtcacct aacccagcag 34380 ttaggtattt cttgaatatc tgatacttaa aacttaactc ccctctacac ctgtgtcctc 34440 tccatacagt aggctaacat caggcagcca gtggcatggg cgccctggct ggcttcatgg 34500 ggcacactaa ccttgcacat cattttcttt atcttctcct ctctcctcct tgtccacttt 34560 tcttctgtcc caattcgctt tttcttttct tacttcatta actctttttc ctttccttct 34620 aatacctcag gaagcacgct taggcattac cttgtcctca gctgcatctt catttaccct 34680 tcaggtgaaa tgtggttgag caaggaaggc aactcgttcc ctacaagtct gagaatgggt 34740 ggagcaggca agagaaacgg ttaaatagac cccagagaag ggctgcagtt aatgataata 34800 ggatttctat ctgtccttcc actgtaccaa gtgacttcca cacagtggca ttttccaagg 34860 gtgagtgcag agggagtagc tgctcagctt ggatgggtat gggcaggaga ggttactgag 34920 gctgcaggct tagcaaggtg agtatgcatg gatcccacga agtcaatgca aaagcaattt 34980 gaaaatccct gcttttcaaa taggtgtaag ggtttctgtc catgacaagg ctgttctact 35040 tcagtctttt aaccatgtat ccacacagtc ccagagatgg tcactagtgt cttcctcacc 35100 tttaacttcc tccttggaaa taattttcac atgctacgtt cttgacctac caggacaaat 35160 tctatgaatt cttcacgtat gtgtcctggg aaggaatagc caaaagcttt gacaagaata 35220 actaagtctg ggctgggtgt gatggctcat gcctgtaatc ccaacacttt gggaggccaa 35280 ggcaggtgga tcacgaggtc aggagttcga gaccatcctg gccaagatgg tgaaacccca 35340 tctctactaa aaaaaaaaaa aaaaaaaaaa atacaaaaat tagcctggca tggcagcggc 35400 cacctgtaat cccagctatt caggaggctg aggcaggata attggtcgaa cccaggaggc 35460 gaaggttgca gtgagccaag atttgcgcca ctgtgctcta gcctggccaa cagagcaaaa 35520 ctccgtctca aaaaaaaaaa aaaaaaaaaa attaagtctg aagtacccag gacttgttga 35580 aatgctgcct gatcatttct ctcagaaaac taacagaaaa ccacattatt ttgaatattt 35640 ggaaatgtca atgtcactca gagtgcacaa cattcgggat taactttttt tttttttttt 35700 tttggagaca gagttttgct cttgttgccc aggctggagt gtaatggcgt gatcttggct 35760 cactgcaacc tctgcctcca gggttcaagc gattctcctg cttcagcctc caaagtagtt 35820 ggaattacag gcgtatacca ccatgcctgg ctaattttgt atttttagta gagacaagac 35880 ttctccatat tggtcaggct ggtcttgaac tcccgacctc aggtgatccg cccacctccg 35940 cctcccaaag tgctgggatt acaggcgtga gccactgcgc ccgacccggg attaacttta 36000 caaccaaact tgatccaact tctaattctg taagaatacc atttctttac atgacagatg 36060 gaataattgg ccaataggtc taaagtctgt cctttattgt gcaataagag cctcgcaaag 36120 gtggaatgca acctgagatc ttaaggtcct ggtctctgtc tttcattttt gggagcacag 36180 atgtaactgg cctttcatca atggtttagt agtgttcgtt attaaattct ataacagaac 36240 cacctcctat gaattgactg tcacatgtct aaatgccctg tttatagcat gttttacctg 36300 agagagcagg ataattactt catttaaatt aaaaacatat ttttatggga atgacccatg 36360 gtagacactg gatacatgtt gaattaacgt gctcaagaca taaaggacgg atacagattt 36420 ctcaatggta aaggcaatat gtagacatct ttgctttact tttaagcaac attccataga 36480 tattgtcaat aacctgaaaa ttcccagaat aatgttttaa atgacttctt aattagcgtt 36540 ccttattttc atacaggcac actcatattc atttgctaaa aacaattatc tgcatgcaca 36600 agttcagggt cccaaataat tctccctggc agattttgtg tgtgtgtgtg tgtgtgtgtg 36660 tgtgtgtatc tgtgtccatg tgtgtatcgc agtgttttga gtgcatatcc tgttttcaca 36720 cacattctct gaaatgttgg ctcattctaa gggctgttgt ttcatttcga tcactgtatc 36780 ctgtggactc tgaaactgct acaaatgctt cttcaccaca catcttatca gcacagttgt 36840 gtgccttttt gatctaaagt tgtgatgaat aagaggcttt acttgttgcc taatttttaa 36900 aaaacttacc aaatattaca tttcccctta taaaataatg atatagatta gtgtttgtgc 36960 agaagtgttg gcaacagaat tcttcaaaag ttttccgttg agtgatgaaa agctgttata 37020 ttattttgac tagctaatca aatgtaattg gggagcttga agtgccttag attttccttg 37080 tacagttatc aaagcaggaa atgtaactcg cagagctgat gaaagccatc tctcatggta 37140 ttctttcaat tatagatctt acagagcaaa tgaaagaaaa gctctactgc taaaaactca 37200 gaggcttgaa atgcccctta atgttaactg ctgtattagc tagttaacac attattatgt 37260 actttaattg attcttactc cagctttgga gaaaaaaatt atggatctgt ttggcatgta 37320 aattaaggtg gggggaagac acctgagtgc aataacagca ctattgctat taacacttag 37380 ttcaagtaac atcagatacc tgcagtgtaa acaatggccc tggttcactt tggcgtgttt 37440 tttttttttt gagatggagt ctcattctgt cacccaggct ggagtgcagt gtcgcgattt 37500 cggctcactg caacccctgc ctcccaggtt caagcaattc tcctgcctca gcctcctaag 37560 tagctgggat tacaggcgca tgccaccaca cccagctaat ttttgttttt ttttagtgga 37620 gacagtgttt caccatgttg gtcaggctgg tctcgagctc ctgacctcat gatccacctc 37680 cctcggcctc gcaaagtgct gggattacag atgtgagcca ccgcacccgg cctaattttt 37740 gtacttttag tagagacggg gtttcaccat gttggtcagg ctggtctcga actcctgacc 37800 tcgtgatcca cccaccttgg cctcccaaag tgctgtaatt acaggtgtga gccaccccgc 37860 ccggcctaaa agcattacta tgttgcactc atctgttggt attcctgctg atgagtgtta 37920 ttgaaggagt tttatttgac cattgagaat tgcttttatg agtttatcaa tgaagtgtta 37980 taatctagta aaaataactt catttcagtc atatttggaa gggtccagct gagattttta 38040 gcttttgaaa ggatcaaacc acattacacc tgcattttac tggggtgtag tatttttctt 38100 tgttgttgaa tcacactctt aaagctgccc ctaaaacatt tcagccataa atgggtagtc 38160 ctgacctagg atcaggccaa attcaaattt tattcacata ttcatttatt cactcacaca 38220 ttcatcaaac atttatcaag tttgtactgt gtgtcaatcc ctatgctaaa ttgctggaga 38280 catgacagaa gcaagtgctg taatcccagc actttgggag gctgaggcag gaggatcacc 38340 tgagttcagg agttcaagac cagcctggcc aacatggcaa aaccccgtct ctactaaaaa 38400 tacaaaaagt agctgggtat ggtggcttat gcctgtaatc ccagcaactc aggagtctga 38460 ggcaggagaa ttgcttgaac ctgggaggtg gaggttacag tgagccaaga ttgcaccatc 38520 gcgctccagc ctgggcgaca gagcgagact ccatctcaaa aaaaaaaaaa aaggacgaga 38580 gccgtcttca ctttacaagt taagtcttca tggcagtttt ctcaattaaa gtagaacccc 38640 tcctgacatt gatgcggcac taaacacaat ggcaaactct gaccctgaaa tcttgtgcaa 38700 gtacttggtt atgacagcac actaataacc ccagccctgt ttacaccaat gtttaagatt 38760 atgtttgaac tggaaaggac aacttaattc ccatagacaa caaggtgaga gtaagggagg 38820 gttcagggcg gcatcactag gagagaacag ctcgtgtaaa aatacagagg ctttggcata 38880 gcacttcttg gaaacttcaa gtaattccta tggctggaag gacaaggata gggaaggggc 38940 aaggggtaaa gctggacagg tgagcagctc atttatacat acggttctaa tatggatttt 39000 attcaaagca aaggggagcc actggaaaaa cttaagcatc gggggccaga aggattgaaa 39060 atgtaccagg gacatatgcc caccacataa tgtcatgatt tcggtcctgg tataggattt 39120 tccttaattg ccagcattta gcttaaagtg catttaaata ttgttttgtt tttaatttac 39180 tatctaaact tgtactaaag gagttggtat cttttatgtc cttagttatt tttgttattg 39240 tctccaacag acctttttcc tctaggtaaa ttttggttat tgatgacatg tatgtatttg 39300 aggtcctggt ccttgtttca tatttaattt aaagaaatgt aatgttttaa aaattattta 39360 tttatttatt tattgtagat atggggccta gctatgttgc ccaggctggt ctcaaactcc 39420 taggctcaag caattcttct gcctcagcct cccgaagtgt tggggttaca ggcttgatcc 39480 accatgccca gccttcagat ttcttcagta taacattctt tttgaccaga aagttttctt 39540 tttctttttt agttttaatt tttttattgt tttgagacag agtctcactc tgtcacacag 39600 gctggagtgc agtggtgtga tcttggctca ctgcaacctc tgcctgggtt caagtgattc 39660 tctagcctca gcttcctgag aagctggcac tacaggtgtg caccaccaca tgcagttaac 39720 ttttgtattt ttaggagaga cagggtttca ccatgttagc caggctggtc tctaactcct 39780 gacctcaggt gatccaccac ctcggcctcc caaaatgttg ggattacagg cgtgagccac 39840 catgcccagc caagtttttc tttttaacct tgaactgatt tattgctgat tatttcatag 39900 ttattatttt aatgacacca aatcatcctt ccagtatatg cacacatcga gggggcagtc 39960 tagcccagtg tgcctaaagt gattccacac tagcttttta aaattacata ttcccaaatt 40020 ctaccccaga cctgatgaat tgctcatcca ttcatatatt tattaattca acatacatta 40080 attaagtatc cagtatgtgt caagccctgt tctagaagtg ggaagaaaca agtgaggagg 40140 aagggagcag ttagaggggt tcagagaaga ccaatgtgaa gagctgacat ttcagctgaa 40200 atccaaataa caagaaagaa aacagccttg ataaatctgg acacacagca ctacaggcac 40260 aggaatagca tatgcaaaaa tcctgaggta gaagctagct taatattttc aagaaaataa 40320 aggaaggtca ctacctaaaa atcaatgatt gtgggggaaa tagggctctt gaaaatgtca 40380 aaaagtttga caaggtccag ctcctggagg gcttggattt tattgtttgg aataggaagc 40440 cataggagga ttttaagcaa tggagtgatt tcatcgaatt ctcagtagaa aaactattgc 40500 actggctgca gatgggaaaa aagttgaagg gaagcaagag agtatacagg aggtccatca 40560 ccccagggga gagatggaga gatggtggct tagatcaggg caggagaatg gagatggggg 40620 agaagttgat ggacccagga tacatgttga ggtaaagctg atagaatttg ccaaaaagac 40680 tttgagagaa gatgaggcag gcaggactca ggtttttggc ttaagccttt gggagccatt 40740 tgtggagaag gggaaccaga ccatctaggg gaaaatcctg cacatgttct aaaacttccc 40800 taaacagata gagccaggtg ccagagccag ttctcagatg tcacctttgg gaactattca 40860 tttattctaa tccttatttt tattcaagaa ggcacagctc gaccactcca cgcagatata 40920 aattcaagct cttcccaaag atttctcagg ggtggggatc ctctatacat tccctgccat 40980 ctatttaatt aattatcttt tttttttttt ttttgagagg gagtctcact ctgtcaccca 41040 ggctggggtg caatggcacg atctcggctc acagcaacct ctgcctcctg gggtcaagtg 41100 atcctcctgc cccagtctcc tgagtagcag gaattacagg tgcccaccac catgcccagc 41160 taatttttgt atttttagta gagacagggt ttcaccatgt tggtcagggt gatctcgaac 41220 ttctgacctc cagtgatctg cccacctcgg cctcgggatt acaggcgtga gcccccatgc 41280 ctggcccctg ccatctattt taaagtttgg cagtagtcaa gacattcttt tatgtacaac 41340 ttaaatcctt ccttctgcat cacgtgtcat tccctgtgga cctgtcaata gagatggaac 41400 acgtggctac cccttgcttc atcataaccc tttacatgat gacttgctga attgcagcta 41460 tgtgaaaacc taaaaaattt agacattagg gaatctaaat ttatttcagt aattaagaca 41520 gaggggtata actaagactg atcacctatc tatgcagcca taaaaaagaa cgagatcatg 41580 tcttttgcag gaacatgggt ggggctggag gccattatcc ttagcaaagg aacacaggaa 41640 cagaaaacca aatacctcat attctcactt ataagtggga gctcgctgag cgcggtggct 41700 cacgcctgta atcccagcac tttgggaggc caaggcgggg agatcacttg aggttgggag 41760 ttcaagacca gcctaaccaa catggagaaa ccccgtctct actaaaaata caaaattagc 41820 ctggcagggt ggcgggtgcc tgtaatccca gctactcacg aggctgaggc aggacagttg 41880 cttgaacctg ggaggtggag gttgctgtga gctgtgatcg tgccattgca ctccagcctg 41940 ggcaacaaga gtgaaactct gtctcaaaga agaagtggga gctaaatgat gagaactcac 42000 gaacacaagg gaacaacaga cacgagtctg cttggggctg gagggtggga ggagggagac 42060 agcagaaaag ataactacag ggtgctggac ttaatacctg ggtgataaaa taatctgtac 42120 aacagacccc catgacaaga gttcacctag gtaacaaacc ttcacatgta cccccgaacc 42180 taaaataaat gtttaaaaac acacaaaaaa gactaagtgc ctatgcagac accagtgtgc 42240 aaattcagtt ggctacgtat gcagagaaat aatggctgag aacatttagt gcttcctccc 42300 ttgaagttcc tgattctgag gttggctctg agctcaggaa actttgcact ccttgtattt 42360 aaagtgtgaa atattacctt taaaggtatt tttctccttc agtatgaaac ctatagatga 42420 atttcatccg atgtttgcat cagtgtcttg gcatagaccc aatttgtttt cctttgttgt 42480 cctttttatg agggtaaagt tgctagttat tttaaatatt ttttgtaagc tttatcttca 42540 attctttaat gatctttgtt gctttttaaa gaactctttc aactttcttt tctatagtag 42600 cacaagaatc caagctatag tctttccaag gcttctctcc tcctggggca gagcagtgtc 42660 agggtttgga ttagaaatca aatccaggga tttatctaca aaattacaga tgagcataaa 42720 tatgtcatac atatcagaat caataaccct gctaatagca atgagtgttt catctattat 42780 aattcttcag tctcccaata ttccaacagg acttagtttc ccactacttc gaaacttact 42840 taatttactt ctagtcattt ggaaaaaaaa attgataata ttttgtctga tatctttgaa 42900 gttgaaaagg cttcttgcca gtttacttat tagcccaagt cagtggtccc ttgcagcaga 42960 gattaatccc agctttgcgg actctaaatt ttatacaatt taggaagcgc tcagtgaaaa 43020 agaccacaaa aatctctttc ttttgcacat tttacaaaaa cattagacct ggagcataca 43080 cattgcttga gtccctcaaa aagccatggg attttctgtg caagtaaagg ctgctgaagc 43140 tgaagctcat tagtttcagg taaatctgct tccgatttgc agttctgcta aggtatttct 43200 tgtgtagaat atcatttggg ctaggaggag gtagaaataa agatagaaat ctacacagat 43260 gatgatattt taaaatttgg taaaatagga tttaagtcta tactacccaa actgactgaa 43320 aataaatatt aaccccagac atctgtagtg agtttttctt tctaaaaata atttctcatt 43380 gacccaggga ctatcaagaa agtcatgcct ggagactaaa gaagtaattt ttctctgagc 43440 taagttcagc atttatagcc tcattagaca ctctgtggtt attcagtctt aagcattcca 43500 ccttctccta agctcaccta gactagctga taccaggcat agtcccatta gttcaatttc 43560 actctcctta ccctaagaaa tttttaatat gtatatcaaa caaatttaaa tggaaaatgc 43620 tgtaagttct cttttagttc tgatgaagaa tttataaaca attcatattc tttttttttt 43680 tcttttgaga tggagttttg ctcttgtcac ccaggctgga gtgcaatggc atgatctcag 43740 ctcactgcaa cctccacctc ctgagttcaa gcaattctcc tgcctcagcc tcctgagtaa 43800 cacggattat aggcatgcac caccatgctt ggctaatttt tgtattttta gtagagacgg 43860 agtttcacca tattggtcag gccagtctca aacctcaaat gatccaccca cctcagcctt 43920 ccaaagtgct gggattacag gcgtgagcca ccacacttgg ccaaacaatt catattctac 43980 aatagcaata tagtattgca tatagataca agttttacta ttatctaatt aggaaactgt 44040 ggggtttcct atggtaagat tataaagtat gtcataaagg ttttggaggt cctcatactg 44100 cagaaattta atttttctat tcgtaaaagg aatcacatta aaaactacta aattatctta 44160 catttcctat ttgattttat ttacccagtc ttgcccttca tgccaaagta aaaagattag 44220 aattcttaag tgactaatta agaggaacat tggaaaacat aatctctaat tatgtctcaa 44280 tattacacgt gtccatgaat agttatctct aagatgaact ccatttggct ttaaaatagg 44340 atgttagaga tatttttatg aaaagtttgc tctccagagc tgtaagttca acataaattt 44400 ggaaggctaa gggaaagttt ttttttttta agtcgtcttt attcacttct aattttgccc 44460 gaaaaataaa gtgacatcct taagtacttt tcatttgtga ggtagtttga ctgatataaa 44520 ttgtgcaggg tagtagtttt gtatacagtt ggttttaggt aatttttccc aggcatctac 44580 tttcctgttc ataataagct gtcagtatat gttagttaaa tgaatggatg gcagagcccc 44640 tttgtgcatt tgctgtgggc ttcggctttc tcggtctttt ggtttgagga atagttaagg 44700 cacacagaga aggtagccta gcaaatctta taagccagtc atatttggga gtgtctgagg 44760 atttttattt ttaaatcatc tacaagtcaa gaatatatac tttaaatgaa atgatcagcc 44820 aggtgctgtg gatcacacct gtaatcccag cactttggga tgccgaatta ggaggatcac 44880 ttgagcctaa gacaaggagt ctcagcatag tgaccctgtc tctacaaaaa atttaaaaat 44940 tagccaggta tagttgcatg catctgaggt tttagttact tgggaggctg aggcaggatg 45000 atcgcttgag ctgaggaggt ccaggctacg gtaagctgag attgcaccac tgcactccag 45060 cctaggtgac agagtgagac tctgtctcaa aaaaaaaaaa aaatcactca ctgttcctgc 45120 ataataactt ttaatcaaaa atctgttcca accccccagc cccatccccc ccaccaaata 45180 tatacacaaa cctgatttag agctggttta agtggctggc ttttgctctg tgtcaatgtg 45240 ccacgcctgt gtatgtacct gagcagttag gatgcatagc agagtttcag tttatatgtg 45300 caggctctca ggtaaaaggg agaattctgg aagaatctgc agggaatact agaaacgtgt 45360 tggcaatact ttataagaga gagtaaaaat gaatttatct tttgaaatgg gagcaaagct 45420 acctattttt ccagatatat acgtcctttt acaagtcgtc ctttttagag caattgactt 45480 ctttggtttg aaattattta cccagatggc tgcctaacga gaatttgaga ttaggtcaaa 45540 tcatttgtag gactattttg attaatgttc tttgatttct aaatcaaatg taccagacca 45600 aacactttca aagagaggaa ttaatatcca caaaatatta tttcatatgc ttttgctcta 45660 ggtttttcca cagctttcag ccctgtctca tttcacctta ggaggtagag aaaaataact 45720 aacacatcaa taattagttt agacctgaaa acactctgct gcacagctgt aatgtttcac 45780 aatggtttct gagctaagag gtgtttatgt agcatcaact ttatcgaaac aaaaccctag 45840 gtaaaaacac attgaaatgg cacttaaaac aacaacagtg cccaaaatct gttgtttcat 45900 tacacttgag tataaggcaa atctggaagt taaattgtcc catattgaga ataactgaat 45960 aaatgtttac ataattgctc ccacttttgc tgaatctttt ggtttgatca ggtttagagc 46020 agagaggtaa aaaatacatt tattaaaaga gagcttttga gattgaatgc tctaattaac 46080 tgctaattac ttctctaact aggctatttt agattaaaaa cctaactgtc tcaattctag 46140 tggattttga ggttgtgatg aagagcagag ccgatattca gtgggaccac aggatcaagc 46200 actgcctgtg ttactcagta tttctctgct cagagacaga accaattata atatttagca 46260 gatttttttt attggaaagt cttaaaaatt gatcagtttt aaaatagatg cacacaaact 46320 accttgagct ttactttctg atgaaaacaa tctatactat atgataaaga acagatagat 46380 atggaatgct ggttcaagct gacaaaatat gcacttttgt tgtcttagat ctagtgagga 46440 aattgattca tgtttggtat gactatcttc acaaggaatt gcttataaag aggtagggcc 46500 taactcattt atataaatcg aggtaaagga ataccaggag taaatctagg aaaattaatt 46560 tttctgtttt taggtgcttc taatactggg aaaccctatt ggtttcaaag ggaacttcta 46620 ggtgagacca tttttagaga acttgtattc cagcaagcaa ttttttatgg agcagaggaa 46680 gcatttttaa ttattatata ttctaaccat attatatagc aatcagataa atttaaagtt 46740 atagtctgtt gattaataaa ttcatggtgg gttggctata atagcaattt tgcttcagta 46800 tctaagacaa aatttgaatg atttgagaat gcatgattta cctcataatg tgacaccctt 46860 ttaatcaaaa cacccgaagg ccaaataatt agatcttgta taaaacttgg aaagaaaaca 46920 ccgttgtata cccctaccca ccattgaaat ctgtttttag ttaataagga agtgggagta 46980 aaatatttga gtgagcctat atataggctc tcatgtatta aaagaaaagc tatttacaac 47040 tgatttgttg ctaaataaaa tcttggatga acacttttaa ttactaaaaa ggtaaggtta 47100 caataaacac aggaaatata aatgaataaa gtgtgcacag agtcatgctg ctttcaggac 47160 tataaatagc acctccatct ctgctactat tattagcaag tatgaacaaa agaagatgtc 47220 cagaaataga aaggggaaga gcatctccat gagccttgta ttccatggca taggaaatgt 47280 ttctagcaag cccgtgaatt tagagggtta attgattttt agaaaggaca tttccatgct 47340 gtcaatttgc caaggaaatt cttttaccag catgtttgta aaattggcag gctgatgttt 47400 cctctaggtg acacaagatg tgatgaagaa ttttatcttt acttccttac gaaaatcagc 47460 gttgattgct tgcctttttg ttaacttatt tggttactat tagtttgcat ctacagagga 47520 tcagttaaca tagttgaaac tggaagaact agtgcatcgt gaacagccct gaaccaaaag 47580 tcaggtttca gtttcacctg agccactaat gtgctctatg actttggtca aagcatttac 47640 atacatatat atatatatat atatatatat tcccctttat atatatatat atatatatat 47700 tcccctttat atatatatat atattcccct ttatatatat atatatattc ccctttatat 47760 atatatgcgc acacatactg ctgtcccttg atatctgtgg gggattggtt tcaggacctt 47820 ccacagatat taacatctga gaatgttcaa gtctctggta taaaaatggc acagtattta 47880 catataacct cccatgtact ttaaatcatc ttaaaattat aatacctaag agagtataag 47940 tagttgttac actgtattgt ttagggaata atgacaaaaa agtctgtaca tgtttagtac 48000 agacacaatt tgttttcccc aaatactttt gatccatggt tgaatccacg gatgtagaag 48060 atacagaatc acagatacgt aggccccact gaaacacaca cacacacacc acacacacac 48120 acatatgcac acacatcttc tctgagccac agtttcttga ttaattaata tagcaaacat 48180 atatggagcg cctcaatatg ccaggcacat tgctaagcag cagggatacg aagtcggtta 48240 agatacccag tccttgctta ctagcctcgc actgctggga gacagacttt tgaacctgta 48300 attagaatgg gcaatgggtg tataacagag acgatagctg ttataagaac acagggcaga 48360 gcttttctgt ctgtggaggg ggcaccaggg aaaactttgc agagatggtg ccatttgaat 48420 caactcaatc ttaaagaatt cctcttgaat ttttcttcaa gactgatttg gatgaaaatg 48480 gctatacttg gtcctcgtga ggaatcaatg acataataaa agtatgctaa aaagcataaa 48540 aaacaatata aatagtctat tagtaatgaa atgattcatg ggcatgaata ttacagatct 48600 agttctaatt tttgattgcc tgtttattaa tgtttttttc tttttgataa tgaattatga 48660 gtgcagttat ttgagaactg attgtaagac tgtagttaaa agtgggagag gccaggcaca 48720 gtggctcaca cctgaaatcc tagcactttg ggaggctgag gtgggaggat tcaagaccaa 48780 catagcaaga ccctgtcttt aatctaaaag aaaagaaaaa aaaaagaaaa aaaaacaaga 48840 aagagagaaa gaaagaagaa aaagggccgg gtgcggtggg tcacgtctgt aatcccagca 48900 ctttgggagg ccgaggcggg cagatcacaa ggtcaggaga tcgagaccat ccttgctaac 48960 acagtgaaac tccgtctcta ctaaaaatac aaaaaattag ccaggtttgg tggcgggtgc 49020 ctgtagtccc agctactcgg gaagctgagg caggagaatg gcgggaaccc aggaggtgga 49080 gcctgcagtg agccgagatc acaccactgc actccagtct gggcgacagg gcgagagtcc 49140 atctcaaaaa aaaaaaaaaa aaaaacacga gagaaacaca aatctcaaac actttaattt 49200 ttttttttta aatcactatg gactggaatt aaaaaaaaaa cttctccaaa tatggatata 49260 ttttcccata agtagtcatg atagactgaa tgattatttt ttaaatagtt acatttttag 49320 gggtttacac gtgaaattat gaagatatgg aatttagtaa taattctttt taaaaacatg 49380 tattacttat ttataaacta tatgtgtatt ctggtgaaag attgtcctct aggaaaaata 49440 agtcttagaa ttatttctct ccagtaggaa tttattattg tcctatcttc agccagacag 49500 ctctgtggta atttcatttg gtgatctctt taataaatat tttttggagt gcctattttg 49560 tgtgatgcca aatgaagtaa acagtgtttt atgtaatatg ttccaatata tattttttag 49620 aatgaaccat ttaccaagta tacataagtc agacattgac tgcatatccc actgaacatt 49680 tccattaata taagtggaaa aaggaaagcc gctttgcaaa aaaaggaggc ttttttgctt 49740 cagcaatatg caaattaatt tgaagcatgc cagtagtttt aatataggtt gattcagaat 49800 taccattgtg aataacattc acttctatta ctgcttttgt taaaactaag cgccaaaaaa 49860 ggaagcctct ttgcttcagc aatatgcaaa ttaatttgga gcatgcaaat agttgcagca 49920 tgcaagtagt ttagaattag actttcatta aaactaagtg ccacacagag aagaggtgta 49980 aaacagagta gtaatctgtt gcgtgcactt gaagggttct tgaaagacgt gcataaaccg 50040 ttaccgttgt agcacaagtt gagcagcaaa agccaaagtc gcacatctgt gtcttgtcgc 50100 cacctctcca cttatccact catgctggct tttctcccag cagctctttg ccctcctcct 50160 tttaacactg tgggctgagg tgaggatgtt ctagtcaaga gtctttacga gccttatatc 50220 gccaggcttt cagaaaatgt gaagcatggt agtgtgaatt tagaaaaaat aaaagtgtgt 50280 ataaaagctc ttctgttttc ttttcttttt tttttgttaa gaaacaatag tgtttattta 50340 tcatgttttg cttagaattc ctttggtatt ctgttctctt gattttaaca agaagctaaa 50400 ctcaataaca tcttttaaaa acaaaacaat tttcggttga gggtgggtga ggaagttata 50460 tgaagattga gtgggaacct caacccaagg acataataga caagaaacag tttttttcct 50520 cccctttctt cagaagtagt cttccgcatg gtttaatgtg ctaacataac cccggttcca 50580 atatttcaaa agatacagaa cttcccagca tgatgataaa gttttcctgt gttccaataa 50640 taaaacctca acgtaccagt gatttccagt tcctttgtgg ctcagcaact tgtgaagacc 50700 aactaagtcc taagtaccca gcctgcagta tcagtgtggg agtcggaaac agatgttcac 50760 gggacaatgc catttgttgt cactgtcgat actatgtggc aactttccca aatgaaattg 50820 tttgtggatg gaaaagaatg taagcagtga ttcatgccca ggaatttttt tttttttttg 50880 tctgcaggct aaccgtatct tatttgtttt aaatcgcaga gcattagtgg attaaaaatt 50940 ttaggttaac ttactattat agtatctttt tcattttttg tcctgtactt ctaaaaggag 51000 tgactaattt aggtagctta ctgagaatag taaatacctt acttgatttg agaattcaaa 51060 agcagctgac atcttttcag atttagtgtt ttaactattg agtaggtaca gagttgccat 51120 ttaaatgaac agcatgactt gcttagcatt tttgttaata atttggaggt ttggagaatt 51180 caaaataaac attaagtaga aacatatttt ttggtaatag gtggcattgc atgatcttgg 51240 tttgagattt tcataaatat tacaaaggaa cttccactaa ctcactcact gttagagata 51300 atagattaat ttgtataaat taaatattaa ttatagagaa gtttaaaatg tacttaaaat 51360 gaatttgata caacaaagct acttaaaagt taggtagacc atgtcatgtg acatgtatac 51420 aaactatcct ttttcaagaa aaaacctaac aagcgtttaa ggcataatat ctactacttt 51480 agtgccgttt ttataaaaca taaattttaa tctacaaatg aaagtctttt aaacatttat 51540 tcataccaac agatgcctaa ggccagaatt ataaaatgtt ttatgttgtt ttaaaaacat 51600 atgtatttct cataattagg tttcggcatc acagaaaaat tattttaagg gtcatacaac 51660 aaaatctgac ttttaaacaa cagccaaagg aaagattggt atcacatgta gaggaagagg 51720 tccttaatta agaagcaaat tccggagttt cagtaactca ttttcactag ctaatgttta 51780 ataaattgta ttaggttagt gcaaaattaa ttgcggtttt tgccattaaa accacaatta 51840 ggttgggctg ggtggctcaa gcctgtaatc ccagcacatt gggaggccaa ggcaggtgga 51900 tcacctaagg tcaggagttc aagaccagcc tggccaacat agtgaaacct cgtctctgct 51960 aaaaatacaa aaattagcca ggcatggtgg tgggtgcctg taatcccagc tactcgggag 52020 gctgaggcag gagaatcgct tgaacctggg aggcggaggt tgcagtgagc caagatagtg 52080 ctactgcact ccagcctggg tgacagagca agacttggtc tcaaacagaa acaaaaacaa 52140 acaaactggc aattaatttt gcatcaactt agtagttgtg tggttccgtc ttcctcggac 52200 ttctttttct catttgcaag atggtacgtc agtctggatg acctttaggg ctctcgcagt 52260 ttttgattct agtttagggc tttgacttct gttctctagc agtcactgtt aacattattt 52320 gagtatctga tgatagcttg tactaatttt cccagaaaaa tgcataaaac agaaattttg 52380 catgcaatcc cagggcttca tggactcatt gaagcctagt gatagtccca ggtaaagaag 52440 ctagttaaag aaagttagta tcctcacgtt tctgtgaaga ttcaagcaag catttcaaat 52500 tgctccaaac gtgggcatca gaactttctg attattaaac aaagttgatt gtttttattt 52560 tctaacatat ctacgttaga aatttggcat tgataccagc acacttggag aaggcaaaaa 52620 cacatgagtt ggtccactaa agacttcaat agcacttgga aagagatact cgtgtgtgtt 52680 atgtatggca tgtcaaggga agttacctac atcccagcta ccttgcttta gaacaggaaa 52740 ggaatgaact aaggtgcact tgcctgtctc aaccagtgaa tcaagactga ttgtttgtag 52800 ttattttaat ttatgaaaaa ttcaaaattt aatgctacag aaaagacaat gggcctaggg 52860 aggactatgt taaagtcttg ttcattttct agacccaaca gagaatactt gaatgcacag 52920 aacaactgag gaaaatcata ctttaagtaa caaatacaaa ctagaaatta attctttcat 52980 aattaagact atttcaacta ttaattttct tccaatatac ccctctactt tttttagcca 53040 tttatgggtc attctacatt ttcttaagtt ctaatatgat ctggagaatg tcttggactt 53100 ctttaaagta acttcatgca tgtgctctca ttagatcctt tatttactac cttactttaa 53160 tgttatacat aatacataat aaacatgtga aattcatttt aatgaatagt gtaagcctca 53220 aaaaatttac ttaaccactt ctttgaccta gcaaatttat aagcgatagt aaaactttcc 53280 ttttaccttt acaataatag cttttaagta ctcaggctga caaattcttc atggactcac 53340 ttttatgttt ttcaatttct attaatttct ctgtattaaa gttgaattag atggatttat 53400 gttgcctatt cctggcattc atagcaacta taaggcatga tcaagaaaac agaaattcta 53460 atcctcatgt tacagaaatg gccccaattc tacttgacag aaatgatttc aattagggag 53520 tctctgggct accttttctg tttcaccaga acaaatgtta ttgatataag gggaaatcct 53580 tggataccat ataacctgct cactctatgg agcagagtta cttagagtgc tccgaatccc 53640 atctttgatc tctggcgata tttttctctg ttatgtcact gaggtcacct ggctcatgtg 53700 tgacaaactg cctgcataag tcacagtgcc agtggcagag atttgtaacc atgcccctgg 53760 tccattgcct ttgaattatt tcacaggccc gctgctttac atttacactc tgtcggaaga 53820 tgaacagggg aagggagtaa aatcaagggc agggtctcat cctgaaggac aaggggaaac 53880 aggtggaagg ttaatggccc tggagcgatt ccacaagcct ctcaggcttg atatatgggc 53940 ctggggccta aaacgggcat tggctttcaa agatatatta tttcatttga ggagagacat 54000 tctggagttc ctgcatttgt ctgctgatag atgatcctct gtccacaatt ggttatggcg 54060 tgtgagtttt ccttgggcct gctcccatac ataaaaattt tgctgagctc tccaaccttt 54120 tgcatgcctt taggaatggg accggtgcaa gcccactggc aggctgttgg atttttttgc 54180 tgctatttta gtagttcctt ttgaaccgtg aggcaagtgg ggaatgaaag acacttctgt 54240 tcattcatac atgacttgat aagggtggcc ttgttataaa aaaaaaaaat ggtgaaaggg 54300 atgttaggaa tcaaacatat gtgtcatttt gggaagacag gctcagtcca aaatttagtc 54360 atttgggttt caaaaagttg cttacataaa agctagatac tatcaaatag cttttgactt 54420 tattactgtt ttgcactccc caggctttta gcaaatggct tactctattt ttctttatta 54480 tttccaaaaa gtttgaggtg atttggagaa agaaggagaa cagacagttg gaaaaaggtg 54540 ctttacacag agatccatga ttaatttgcc taacaagaac catcaggcaa tgctaccaag 54600 aaatatgtct aatggctcaa atgttacaat caaatagaac tggtcactag attaatggaa 54660 ccagtcaccc gaattaacct tgtgtggcct ctcaaagttg tactatagag tctaagactg 54720 caaaaatcat ttgcctcagc ctcttaatgt tcatagactt aatattcatg aaaatatttg 54780 gattctaata tgctttgatt tatagtattt tgaaatttaa ttattaactc tggtttgaga 54840 tatatatata taaaatcttt gattttatag ttcctggtaa ttgtgatact agctttgtca 54900 gagagagaat gcttatttta tggcaagcat taaggaaaaa tgagctctgt aaactcacta 54960 tctaaacaaa aggcgatttt tctttccagc tcttttgtgt tccattaccc ttgtgtttgg 55020 tgaattctca caccactgta tgaaatatca aaatcctatt tgtggacatt ttatctcgaa 55080 tagctttgtc aaaaacaaat tcttcacctg gagaaacttt ccattatcat cacagataca 55140 ctggcattta actacaagaa gttaatattg gacaaatgat cagataatat ctgagtatca 55200 ataggaattt cattcttgga tgagaggcaa caaattgcaa atacttttca catatattta 55260 caagggatcc ttatcacaat ccctattcat attgccctca gtagaaacat gcagcatctg 55320 gccattggcc cctgttaata atgattacac agatgtcctt ttcttttcct ctggaatatt 55380 gcaaagtaga ggttagacca gaagcaagaa gactggagag gcatgtttag tacctgcaag 55440 aagatattta ataactttct tagaggaaag attcagaatc accagttaca ttgagttgaa 55500 tgaggagcat tagccgtcaa aagaatctgt ttttccactt gttgcttgga taaatggata 55560 aaagcctgcc aaggacttca gtccaccagc tgagggtacc atagctaaaa tactcccaac 55620 agaagggcag gtcccaaacc acacaggcat gcttttcaat cacagaataa aatgtagttg 55680 ttttcgtcat ttcagcttgt gacctaaatg cctcattttc atgtttgaaa agttaccaac 55740 tttatttcag tcctatttcc cttcctctgt ggtatttccc agtcagtaga ccacagtcct 55800 gtgggttata tcaatgccta aagcagagat caaatcaaag cataccacat aactggttaa 55860 aatgaaagct cattccgaat tagtaaataa tgcccgcctg tcttccacat ctgtcaaagt 55920 ctcccagctc agatggacac ctccataagc tgatccatag gaagccaaat acttgcaaac 55980 agcctcttaa ttgctcattt gcagttggac aaaatgctaa atgcagaaag acttcaaagg 56040 caatggaatc tgcattgaaa acaggatctc aatacacata gtcgcttatt gttgcaaaat 56100 tagaataaca aatgttccca gcatgaagcc aacataaact tgcctgagta ttattcaacc 56160 tgaaacatag tctacctttt tttttttttt aacagcaata gaagaggcat acttagcact 56220 ctgtttgtta ttctatactg ttcattttaa tgatatattt aggtctccct gacactttgt 56280 atttttacgt gtaattaccc atattaaaaa aaaaacacca ctcattagtg ttctgttcta 56340 ctgacttaat tatgcccctt aattaaatct cagctaacag ggggtcaccg cagtgtcagt 56400 gggatttgtc actgtttgtc agcaggtgtc tggttgcatc tatttctggt tttcgtatgg 56460 tttgaatcta tttaagaact tgctacaacc ccgtcctccc ctccacacca accccaaatg 56520 ccagagacag cattctcatt ggagggaaga agcagtatct atttgacagg caactgcttc 56580 ccaaaagctt gtttgtaaga ggaaattttt gttttcatta ctctagaaaa aatctcctga 56640 ttaggggaaa gatgcttaaa acagacttgg ataaaacaga tgcactattt aaaagatgaa 56700 taggtttaca ttctaaaaat tatgatcata tttttgtata caattctaaa agttccttga 56760 agaacaaaaa atatattttg ttgctgctgt tatgagaaga acatcacatt aggtgttttg 56820 catcatctgg ccattggtgt ctttgtacag agtactttgt atcaattatt tggttcacgt 56880 ttttcatttt aagaatataa aacaaattac aaacatatga gtcaaaccga aaaaaatgtc 56940 ttttgtgtga ctaatgtagg gtcaatagga atttaattct tgaatgagag gcaacaaatt 57000 acaaatactt attatttgga atgagtctta gtattaagac ttatatgtct tcacatttca 57060 cattagaatg ttttaaactc atgattttag tatattaatt aagggagata taattcccat 57120 gtttctgtat ataataggca tctaatgttg atctgaataa ttgattagtc cagtcaggct 57180 tttataatta gttgtcagct tttcagtgta aagccctcaa aacacctgct gtgcatctac 57240 aaaggtctta catatttatt agtgttttta acctaaaaag gcatgcaacc tacctgaaaa 57300 gcatttaatt ttttttctgg aactaagatg acccttccaa catataccct aagaaactaa 57360 ggctatatgt ctctgagttt ttcagtctag aagattttgg actgaaattc tgatttttaa 57420 aaatcataac acttatcttt atttaaagat aaaaatgtca cagtttttct atggaagttt 57480 ttcagaactc atatttctaa tagtaaggtt aagcaagaca atgggttaca gatatcaaac 57540 tatcaacaat gtaaagtagt tttgagactt cactgtcatt attgtataag caattttatt 57600 tttctgggtt tacctacaaa tgtggtagtc acagaagaag aaaaataatt taaagaaaaa 57660 tttataatac tcagcttatt tatttctgaa attcaaatca attcatttca tcctaaaaag 57720 ttaactccaa ctggcttttc ttaagtaaca aatgtcatca tttgctgtcc aagtaatttt 57780 caatacaatg ctcatttgat gttgcctcta aagttcttat cacacaagta ataagtaatc 57840 catacattac atatatgtgt acattttaaa aaccatttca aatggtgaga taagaatttt 57900 tatgcatttt atggattcct gtacagcctc ctcattgtca ttagataatg aaaggcttcg 57960 ccatgtgtgt atcgtaaaga cctactaagc aatatgaact ctccagattg ctttacattt 58020 acacagttga agtatatata tatacagtat tgtacagtat tgtacagcaa tattgtatag 58080 caatgtacag tattgctggg cacagtggct catgcctgta actccaacac tttgggaggc 58140 tgaggcaggt ggatcacctg aggccgggag ttcaagacca gcatgacaaa catggagaaa 58200 ccccgtctct actaaaatac aacattagcc gggcatggtg gctcatgcct gtaatcccag 58260 ctacttggga ggctgaggca ggagaatcgc ttgaacctgg gaggtggagg ttgcagtgag 58320 ctgagattac accattgcat tccagcctgg gcaacaagag cgaaactcca tctcaaaata 58380 ataataataa taataataat aataataata ataataaagt acagtttaaa taccataggg 58440 taggtcagat attcttaaga ttccttcttt cattcagtaa atacttatca agtattagtc 58500 gtatgccagg taacattata ggacttagag attcaacatg aagagcatag acaaaaatcc 58560 ctgcttttga ggatcatatt tatatctatt ttagtgacta agagcattta tttaagacaa 58620 ttgcactcat gtaattaaaa agcacttata atctggcaag ctagcctaat cttagcaatg 58680 gaatgtttct gctctctttc tgtttaagcc ttcaggagat cataccagtt ttcccaactg 58740 gcatatggtg agttcaagta catttcccac atatgctcag ggattatctt aattgtattc 58800 ctttctgaag cttggaatca agggaaaaaa agaacaataa tgatttaggg aaaaataata 58860 gttttttaaa ggtagattta tagttagtaa ctttatatag gtgaactgat cacagagaag 58920 ggtgtaaatc atctgaataa acaatggatt ttcacactta ctagaatctc taagaataat 58980 attttccata ttacagctaa atgagaccca ttatgtatgc tttcagataa actcacaaag 59040 ctcttaccca tgtaaatctc atagatctgc cattattcgt aatgaataac aagttttatc 59100 atgcattttc attaaaaatg cattaatccc tttgtagtaa cctctcccta attcattgat 59160 tcgataatac aagaacagta aacatttctg gcataacaaa aatgtggtat caaagcatac 59220 tgtatccata aatacaaaat gtaacaggaa aacaaataca tttatcaaag gaggatcagg 59280 ttttccagcc actaaataat gctatggtcg aatactgcta cagtctaata cattaagaac 59340 tcaatcatag tgccgcattg tgagccgttt gtaccggatc tgattcttcc agattaaatg 59400 acttgttgaa acttgaagat gaaagacagg cagaagtatc cggggctcta ccctcaggag 59460 gctccagggt gggttactgc cagtggggga ctaatgcttc cgtctagtgg agataggagg 59520 aggaggatca gaagtgacat gtatgtaccc ttttttactt gtagattatt tacttagctc 59580 gttttaggct ctgtgtcctc atctgtaaaa catggcatta cctctttcag gtattttact 59640 ggggattaaa tgacttaaca caaattaagt ccttggtaga tagtatatat tcaagaaaag 59700 tcaatttcct ccttccttta ttgatgctta aaagcccctg gtgctgtatt tgattgattc 59760 aacaaatact tgggcttggc acaaggcact ggctatacag ttacttccct cttatcatca 59820 ccatagaagc ctcctgatgt ggaaattagg caggccttgg agtcacactt ggcttcaaat 59880 ccccttccat ttgcttccca taagctcagc atgtaacttc actgtccttc tctaaaaata 59940 ggggtaatgt ataacttacg tggttatcta aaaaattaaa tatttgtaga gtgcagtgtg 60000 ctagaatatc tggatacaga gagatggatt agagatggtg tctagagcac aacagaatga 60060 agacctatct caaaaaaaaa aaaaaagaaa agaaagaaag aaatggtctc tacccttaaa 60120 gagggggata cacatgtaca aaactgtgaa tcccaatgcg atttttgtgg ggaatgtgtt 60180 cgaatgctgt tcctgaacat atatctcagc atttccaaaa caaaaattac atttcagaaa 60240 ctcagtagat aagaaacatc tgcaaaagac cgacacaatt tatcttcaaa ctaacaaatg 60300 tgttgatcta tgtgcatttg atatctctat acttatatag gatgctagga gacaattgtt 60360 ttaagtctgt gtggtgctca ttttctttgc gcctaatgta agagctgttt ggtccatagt 60420 cacctctgtc cattctagaa tagagggtgg tgagatgggg ggtggtgttt ttactcgtga 60480 gtcgtttgga gattatcagg ctaactacgt gataaaagat gctgaaacac tggtttgagt 60540 tagggtggag aaaatgtgac caactcccag agtccagtat gattcactta ctgttgttaa 60600 gactttctgc cttcctttaa ttactatgtc aaacaagcct tatttatgcc aaacaattaa 60660 gtctattatt aatggagagg taagagggtg gggagagaat gagttccgga aacttttttt 60720 ttttattttg agagggagtt ttgctcttgt tgcccaggct ggagtgcagt ggcacaatct 60780 cagctcaccg caacctctgc ctcctgggtt caagctattc tcctgcctca gcttcccgag 60840 tagctgggat tacaggcatg cgccaccata cccagctaat tttgtatttt tattagagac 60900 ggggtttctc catgttggtc aggctggtct tgaactgcca acctcaggtg atcctcccac 60960 ctcagcactc caaagtgctg ggattgcagg catgagccat tgcgccggcc tgacttctgg 61020 aaactttttt agaaataaaa gactcagcta atagactacg atatgttgag tgcagtgata 61080 gaagttccct aaggagagta aaatctcaac aaatgtgagt cctctttttc tctgcaatcc 61140 tgacctgtgc taaaattggg gacaaggccg ggcaaggtgg ctcacgcctc taattccagc 61200 actttgggcg gccaaggcgg ctagatcaac tgaggtacgg agttcaagac tagcctgacc 61260 tacatggtga aaccccttct ctactaaaaa tacaaaaatt agctgggaat ggtgacacat 61320 gcctgtaatc ccagctactc aggaggctga ggcaggaaaa tcacttgaac ctgggaggtg 61380 gaggttgcca tgagccgaga tggtgccact gcactccagc ctgggatata gaatgagact 61440 cctcaaaaat aaaaataaaa aattggggac aatatcgggt agacaaattt tagtttctaa 61500 agtagctgaa gggtctttgt tcaggtggtt tctgcctttc agctttgacc tttatctgcc 61560 ttgttgcagc ccatgcatac tcttcctctt ccaatattca tacatccaca aatgtccctc 61620 tcccttcaac acatacaccc ttcttcacca acacacacac acacacacac acacaccctt 61680 cctcttaaag cttattctca agaaaggttt aagtttgtcc tttcagttca atagccatct 61740 ttcctcatgg agtttgtcag gtcccttctt ttgtaattct cctacttgta ctctccatcc 61800 actttatttc cctttttttt tgagacggag tctcactctg tctcccatgc tggagtacgg 61860 tggtgtgatc ttggctcact gcaacctccg cctcctgggt tcaggccatt ctcctgcctc 61920 agcctcctaa gtagctggga ctacaggcac gcaccaccac acctggctaa tttttttgta 61980 ttttcagtag agacagagtt tcaccgtgtt agctaggatg gtcgcgatct cttgacctcg 62040 tgatctgcct gcctcggcct ctcaaagtgc tgggattaca ggagtgagcc accgcgcccg 62100 gctttatttc ccttttatct gttctttcat cccttagtca cattttattt tttttatttt 62160 tatttttata tattttttga gatagagtct tgctctgtct cccaggctgg agtgcaatgg 62220 tgtgatctcg gatcactgca acctccgcct cctgggttca agcaattctc ccacctcagc 62280 ctcctgagta gctgggacta caggcaccca ccatcatgct cagctaattt ttatattttt 62340 gaagagatgg agtttcacca tgttggccag gccagtcttg aactcctgat cgtaggtgat 62400 ctgcccacct gggcctcaca aaatgctggg attacacgta tgaaccacca tgcccggccc 62460 cttgctaaca ttttaatttt gtttgtttat tgtaattaga gatggagtct cacgtgtggc 62520 ccaggctggt cttgaactcc tagcctcaag cagtcctccc acattggttt cccaaagtgt 62580 tggcattaga ggcgtgagcc atggtgccca gccccttgtt tttttttgtt gttgttgttt 62640 ttgtttttgt ttttttattg aaacaataaa aaactcctct ccatctcatc ccacttgctc 62700 ttgttgccca ggctggagtg cagtcgcgcg atcctggctc actgcaacct ccacctcccg 62760 ggttcaagtg attctcctgc ctccgcctcc tgagtagctg ggattacagg catgtgccac 62820 cacgcccagt taattttgta tttttagtag tgacagggtt tctccatgtt gctcaggctg 62880 gtcttgaact cccgacctca ggtgatctgc ccacgtcggc ctcccaaagt gctgggatta 62940 caggcgtgag ccaccatgcc tgaccgccca gccccttgtt atttaaatct ttcctcttcc 63000 actggctctc atcagtccac atgaatgtgc aaagctcccc tcctgaaaat agaacaccac 63060 attacatggg tctccctgtc tgtcaccgtc ctaccttttc tcatcatgac acctttgccc 63120 ttttctccac ctcttctttt tggtgttaac acagccaata ctgtaggact gcagtgctaa 63180 agccgggcag caagctcact gcatttgcac ttctccatgg gaaatgcctc ttgtgaatct 63240 taaacatcat caaggagctt agccacatct tctcagccct catcctctct ccccatttta 63300 atccttggcc atccttgaaa ttccttctgg cccagacttc ttggtcacta ctcagtactc 63360 ctctctgagt gcaccttgct aggtttcttc actagctcct ctccctctac ccaatcttaa 63420 acaatatttt tttctagttt tctcttattg gtttccttac tttctcatcc acacattctt 63480 agtgatttct cccacaaaca caattatgcc atactttctc tcgcaaactc cacagcagca 63540 tcgtgaattg cttgctgaaa cataaatgat catcacctcc aataagcctc atttagttct 63600 gcaactttgg gttttgtttt gttttgtttg ttttgttttt tgagacagag tcttgcactg 63660 tcacccaggc tggagtgcag tggcaccatc tcggctcact gcaacctcca cctcctgagt 63720 tcaagagatt ctcatgttac agcctcccga gtagagactg ggtttcgcca ctttgggcag 63780 actggtctcg aactcctgtc ctcaagtgat ccgcctcagc ctcccaaaat gctgggatta 63840 caagcatgag ccaccacacc tggcctgcaa ctttgtacaa ctttctttct ttcttttgag 63900 aaggaatcac actctgtcgc ccaggatgga gtgcagtggc accacctcgg ctcactgcag 63960 cctgcgcccc caggttcaag ctactcttgt gcctcagcct cctgagtagc tgagactata 64020 ggcgtgtgcc accaagccca gctacttctt gtatttttag tagagatggg gttttgccat 64080 gttgcccagg ctggtcttga actcctgggc tcaagggatc catcctcctc agcctcccaa 64140 agtgctggga ttacaggcgt gagccactgc acctggccct gtttctttct tgcactgtca 64200 aacaacacat tctctgcagt tattatcctg ggttgtctgg tttgatcata tcactcacaa 64260 ctttctattg catatgcaga aaaaattaga attcctcaac caggtatctc atcatcactg 64320 tcttcctctc catctcgtct cacctgccaa actcaaagcc attgatttga ctagtctaaa 64380 tgtaggcctg gacgtatttg acatggggac tatttgaaat ggggactatt tgaaatgggg 64440 actatctggc aaaatctggg atgggatgta agatgatcgc aattgcacac tcactcctag 64500 cctggtttct gttagttata tgtctacccc ctcaactctt tccaacctct ttcttgtcac 64560 tgtttcctct cacaaactct agcacagagt tttgaatttg gtagttacac cacaaaattt 64620 ttaacttgtc agaaattcat ttatgattat atgcaaatga cttgtgttga tttaaagcag 64680 tagttcccac accttttggt ctcaggacgc tttgcacttc tgaaaatgag gactatggag 64740 acctttagtt tatataatgt attgggagtt aaaaacagag atatggttac aaatcaagca 64800 tccacaaata cacattccat ttgtcaccag agtgatgatg tcattacatc ctgtagcctc 64860 tgcacactcc tgacaagtgg agggtgaaaa gggcaaataa catcttggtg taattggaaa 64920 aatagttgta acctcttgac tccctggacc atactcgtaa agccactgat ttaaatatta 64980 tcactcctat gggtgtctac tctttcattg ggattaaaga ttgatgccaa atgaatacat 65040 tttccaacct tgaattttca aatcagtaag taagatcagg gacatccagg ggaacaaaaa 65100 cccttctcag tgtcctggga tttctctccc agtggctgtg agactgtact cctggaggta 65160 gggggcatca gtgagaccag ggccagtttg aggacagcac agatgtctct aggtaactga 65220 caaacagaca caggtttccc tgagtgtcag cctctgcccc ctccctaaca cacactcaca 65280 ttcacgtaca caataaatca ccctggagtg cgatggaaat tccaagaact tcagcattgt 65340 cttaacctgt gttctggtgc catcctgagc cttgaccaca ttgactggct tttaaagtag 65400 gtgccattgc attcattctt ctgagatcaa tatccctctg ggtctcccca gcagctatgg 65460 tctttctgct tggccccaag acaattaaga gaattaatgg ggagaccatg tccaaataaa 65520 agactggagt tattgcttta acgtgcagca actccagtat ttgcattaaa ttattatttg 65580 ctttgtaata tttgatcaag ctagggttag ggactagact gacttttata gaagagtgat 65640 gcactctaac agtgactact atttattgag ctcaagcctt aagttctatt catttattag 65700 ctcactaaac ccttacaaca aggggagtgg ggagggtcaa tattaattag aatttgactg 65760 cagccagaat aaactaaagc tcagggggtt tagttatttg cccgagttca cactgatctg 65820 ctggccactg gtggagcctg tttctgtacc agacctgtct gattttgcac ctccttaccc 65880 tttgctctct ttcttttttt tttttttttt tgagacagag tcttgctctg tcacccaggt 65940 gggagtgcag tggcgtgatc tcggctcact gcaacctcta cctcccaggt tcaagcgatt 66000 ctcctgcctc agcctcctga gtagctggga ctacaggtgt acactaccat gcccagctaa 66060 tttttgtatt tttaatagag atcgggtttc accatgttgg tgaggatggt cttgatctcc 66120 tgacctcgtg atccactcgc ctcagcctcc cgaagtgctg ggattacagg cgtgagccac 66180 tgcacctggc cccctttgcc atcttagtta ttgttctcat cccatattcc tgtgtctaac 66240 attttggtgt gtgagtgtgt gtggaggact gatgtgcaca tgtggagtgg ggagcattgg 66300 tttgctagaa ttttctagag ctttttattc aaagtgcggt acatgaacca ccagcattgg 66360 tttcattagt cagcttgtta gacatgtaga atcacagtcc cccgaactgc tggatcactg 66420 tgtattttaa caggaccccc aggtgaactc taagtgtgtt caagtttgag aaacatggat 66480 cttgagcaca gttgtatctc tctgaacttt tttgagagaa ttaagtgaag ccattagtag 66540 ggtttcctgc atagacacat attcaacacc tttagtaaaa aacaaaaagc ccgcttctta 66600 aaagaatatg ctttactttg aaagtttgca tttatgctat cttgtctatt taatgctata 66660 taatttcaga cataatatag taactctaca agacctcctt ccctgtataa aaagacgcac 66720 tataagtttt tgtagtcatc tttgaggtct gtctgtagtg tgctttatta aaagcgagca 66780 aatactgaag gatcccattt aagtatgtgg tctgcggtgg agtctaattt gtaccactag 66840 gcaaaggtca cacagaggag ctcgttaatg cacttactcc gggatgaaat caatctccat 66900 acttcaccat attgatctga tagctcattg gcgcttccct ccgtgaactg gttagctcac 66960 gtgtgaatgg agagagatag atagctttct gggcctgaga attctagctg gggtgccatc 67020 cagggcaaaa ggtggatgtt tttacatcct catttgggtg gcccttttgg tttctggtgt 67080 taggctcttg tgctggtata tcagttagtc agaaaaaaaa aaggttttaa aataaataag 67140 ttgcttttct accatgggtt tattcttttt cttctgtagt ttttatgaat catgtgtgct 67200 caaaagtatg gatcacattt atctgaatac aggcagatga cttgctttaa agtgtaacat 67260 tgatattact aaaagacagg tctttttttt tttttttttt tttttttttt gagatggagt 67320 ctcactctct cgcccaggct ggagtgcagt ggcacaatct tggctcactg caacctccgc 67380 ctcccaggtt caagcgattc tcctgcctca gcctcctgag tagctgggat tacaggcaca 67440 tgccaccaca cccagctaat ttttgtattt tgtattttta gtacaattag acttgtagtt 67500 ttagggattt caccatgttg gtcaggctgg tcttgaacac ctgaccttgt gatccaccca 67560 tctcagcctc ccaaagtgct gggattacag gcatgagcca ccacacccgg ccaacatagg 67620 tcatttctta atgaaaagat aacctgctca gtgcaatctt caggactcag gagtctcccc 67680 tatgttcctt tttgtcaaaa ctcaatgcta ttgatgtata tatgtggtca tttaattgca 67740 gaaacaccaa ggaagtaggg cttggtgaat ccggctcata aaacacacac atgggtacta 67800 attccttgaa gaaatgggcc aaaataattc tagaaatgag gtagaaacaa gccaacaagc 67860 caaatatttc caatttttaa aagatgtata gattccagat gcaaactgga taaaagcaga 67920 ctcagatccc ttctaacttt gagacacggt tttccagaga aactatgaat attgagaaaa 67980 cagcagcctc caaagccgcc aagacttgat attttcatta cgcttggtta caagctcgtt 68040 gaaaagtgtt tccggttcat ccttgaatct cttccaatct aagcacaatg ctgtgcacat 68100 gagcaggtgg ctttgtagtc tatagactcc tcctagactt ccttttccta gattttaagt 68160 caaattttgc ctcgaggaag agtttgaagc tcgagtctga ggcaagtatc tagcccaaac 68220 tttcgcaaaa ttgaattaac ctcattcttt ggatgggtat ttctaaattt ttaaaaattt 68280 cttggccggg cacagtggcc cacgcctgta atcccagcac tttgggaggc tgaggcgggc 68340 ggatcacgag gttaggagtt caagaccagc ctggccaata tggtgaaact ccgtctctac 68400 taaaaataca aaaataaaaa tacaaaaatt tgctggttgt ggtggcacat gcctgtagtc 68460 ccagctactc aggaggccga ggcaggagaa tcacttgaac ccgggaggcg gaggttgcag 68520 tgaaccaaga tcacgccact gcactccagc ctgggcaaca gagtgagacg ctgtctcaaa 68580 aaaaaaattg gttttttttt ttcttttttt ggagacagag tgttgatctg ttgcccaggc 68640 tggagtgcag tgacgccatc tctgttcact gcaaccttta agcaaggggt ttaagtgagt 68700 ctcgtgtctc agcctccaga atagctgggg ttacaggcgc gggctaccac acctgcctga 68760 tttttgtgtt tttagtagag atggagtttc accatgttgc ccaggctggt cttgaactgc 68820 tggactcaag cagtccattt tttgcaacct ccgaaagtac taggattaca gatgtgagcc 68880 accacgccca gcctggatgg gtatttctaa aatacacatc tattaaatgc cacttttttt 68940 tttttttttt tttttttttg agaaggagtc tcgctctgtc gcccaggctg gagtgcagtg 69000 gttcgatctc ggctcactgc aagctctgcc tcctgggttc atgccattct cctgcctcag 69060 cctcccgagt agctgggact acaggcacct gccaccacgc ctgacttatt ttttgtattt 69120 ttagtagaga cggggtttcg ctgtgctagc caggatggtg tcgatctcct gaccttgtga 69180 tctgcccgcc tcggcctccc aaagtgctgg gattacaggc gtgagccacc gcgcctggcc 69240 aaatgccact ttgaatgtca aaatatgact gttcttcaga tgaaaaaata gcctttttag 69300 acaccaggca ccaaaataac tttcagaaaa agtagtgttc ttctagagtt ctcatagata 69360 gaaaagaaca taaaggaata tgttaaacat aacaagaaga ctggacatat ttgtaagatt 69420 ccaaatctta ggatataatt ctgtccccag cctttgtgaa gacagatggt cacaatgagg 69480 aagagggtat agtttaccct tcaatcaggc tccatctgac ctccttttta ataaaaagaa 69540 aaaaaaaaaa aagatctcac tgtttcccgg gctggagtgc agtggtatac tcatagctca 69600 ctgcatcctc aaactcctat cctcaagcaa ccctcccaca tcagcctcct gagtagctgg 69660 gactataggc atgtgccatc atgcctggct gagctctttt tgagtaattg aaatagcaat 69720 gagatgccca gagtcctcag tttgaactgc tgtgttcagc ctagtgagaa atgcataggc 69780 acttcagata aagtggcatg agacttcagg gaacaaatat agaacaatgc tgcacaaatt 69840 cacctgacct tgagcacctg gctggatgtc cattggtgaa tgttgttaga tactgtctcc 69900 tacgaatggg ttatgattac tacttggtat cttctaagta aaagtcctta accatcacca 69960 agtaatatat tttttttttg agatggagtc tcacactctc gcccaggctg gagtgcagtg 70020 gtgccatctc agctcactcc aagctccacc tcctgggttc acgccatcct cctgcctcag 70080 cctcccgagt agctgggact acaggcaccc gccaccatgc ccagctaatt ttttgtattt 70140 ttagtagaga cagggtttta ccacgttagc caggatggtg tcgatctcct gaccttgtga 70200 tctgcccgcc ttggcctccc aaagtgctgg gattacaggt gtgagccccc gcgcccggcc 70260 agcaagtaat attttttaaa aaattttttg gcagtgaaaa gtctaatgag acataaagaa 70320 ataataggaa aagtactact agatgggcct gaaaatgctt tggttctcta acttgtgtgt 70380 aatggccaac atcattaaga caaggacatg tgacagacta attttgaaaa tttattctca 70440 tgttactgca tttttgttat tctagttatc aatctacacc cataccacaa tgctgcttta 70500 ttttgtttgt ttgtttgttt gtttttgagg tggagtctgt cacccaggct ggagtgcact 70560 atcttagctc atggcaacct ctgcctctgg ggttcaagtg attctcctgc ctcagcctcc 70620 tgagtagcca ggactacagg tgtgcgccac catgcctgac taatttttgt attttgaata 70680 gagatggggt ttcaccatgt tggccaggct ggtcttgaac tcctgacctc aggtgatcta 70740 cctatgtcag cctcccaaag tgctgagatt acaggcgtga gccactgtgc ctggcctgtg 70800 ctgccttcct gacactcaaa cacaacaggg tatgagttgt atgatcagct atggaaaaca 70860 gactgtggta tgtatgtatg actgatatgt ggtaacaacc cttctctagg cctgtatctg 70920 tctacacaag cagaaactgt tggtcagttc aattaaaaaa ttaactgatt taatgagttg 70980 gctgaattac cttattgttt gacatgagtc aaccagccca ctccagcaaa acagccaacc 71040 aactcagtca ctctgtagaa gcagcgtgtc attgaacaac caaacacaca gtacatcgtg 71100 cacagcataa cgatgcttca taaatgatgg actgcatata tgatggtggt cccaacatat 71160 tataataatg tatttttact gcccattttc tagtaacaca aatacttacc attataagta 71220 ttgcagtgta gaatagtaac atgctgtaca ggtttgtagc ccaggagcga tagactattc 71280 catatagcct aggttcatgg taggtgctac catctaggtt tgtgtaggtt cactctctgc 71340 tgttcacaca aggatgaaat cacctaatga tgcatttctc agaacatgtc cccatcatta 71400 agcgaagcat gacctgcatg catgagtaat tatgtgtgtg agaagccatg agaatacctc 71460 tagaaacaca attcttcttt ctctgaaaaa tgctttccct caaagaacag tgcatgctca 71520 tggaaaatgt aaacgatttc tttctataaa tatcaaaccc attttctctg tgattcatat 71580 ttcaaataaa acacacacaa gatcaacact taaattgggt attatttctt tttttaaaat 71640 aaacctttgt cagaatatta tttcttcttt ttttcttttt attgccactc ctcctctcca 71700 gaatattatt cctactgtgt gaaatccaaa ggcaatggga agggatacag ttctgtctct 71760 ctcccttctt acaagggaga caaaagaact cccttcgtca ctcacctctg ttagaaatgc 71820 attcctttaa tacaaagagt atttctccca ttttatgatg agaataattg ggaaaaagaa 71880 attcaatact ttatctttca cttctcagcc acctttgggg aacttatatt ttgtatatca 71940 ggatggctgt gctatgcata acttcttaca gatcttgata tgctatcttt catcattata 72000 ttcagatata aacccaatag ttgtagagat tactaacagt gagtaaagga aaggctatct 72060 agaaatatgg aagacataaa gggattgtct tgggactgac ctacagagtc cttgcctcat 72120 ggggacagat tcaacagggc aatgctgacg tcttaggaag ggagtgtgta ggcggtgtgt 72180 atgttgggtg ggaatgggaa aggcagtata gtatcatagc ctgcatattc ttctccttta 72240 atctagaata ggaagaatat gaaagtagag gtaataagaa atatgccata agacacaccc 72300 tcttcagaca gtgcaaaaga gctaggtgtg gttttgctaa aaatctagct aatgtgattc 72360 tgatttcaaa atcattacct tgcagcttgt gtagaatgtt ttcccctgtt taactggcca 72420 ggacaaggaa actaaaatat ttgtcaaaac ttgtgcctta caatgttgta aatgatgttt 72480 ccatgtccct ccttttgaga tttaagctat ctagtgggag tgggtgccca tactccaccc 72540 tgccgagctg taagcaattg taagaggggc cactgacaac ttcacctctg agtcttctgg 72600 gactgagacc cagaataaat gctaggcctc agttcatctc ccaaacagaa tcactttctc 72660 ttgtttttcc cccaaatcgg aaggagtgtc tatctagatt ttatgtccag ataattccaa 72720 ggttctatca tttggtatct atggttttgt attttgtaaa cttccaaagg acttcatttc 72780 ccaaatcaca aatttcttta catttgaaat agagaaatca aattatcatt aatgtatttc 72840 tttgcaggaa agaaactggg caatattata ttttaaaaaa ataacttaca gaaaaaaata 72900 ggaagattgt tctttactct tatatgaaag aggcatagtg aaagagcact gggcttggat 72960 tcagaacacc tggattccca tcctgtttct ggcacctgag tagccttata taaaccacag 73020 cccacctagc ctgagtttcc tcttctataa aatgatgtag ttgaacgaaa tgtagctatc 73080 agatactttc agcattgatt cagcaaatat taattaagca cctgcggtga gcctagtacc 73140 agggtgtgat tcagcatgta acaggatggg ggtgtcccca gtccaggtaa tgaaagggta 73200 gaccattcac agtgtcaaag acagaaaact agataggacc tattactctt agcatgctat 73260 gtttagggca ctggcataaa tatttcccac taaatattct acactatcta gaaattttta 73320 acaaagcaaa aattgttgtt tacctagact taatctttct gtagtttagg gccaaacttc 73380 gactgttgga gctccatctt caattgctac tactttctat gaatccattt ctgggaatct 73440 ctgaaggcat agactgactg tacacttagc actgtgacat taaggggaca tttaaattgt 73500 gtgaagggac aagtcctcta cttgtccctg gggaactgag cagaggaatt ctcccaggag 73560 cctttgtacc cagagaattc ccatcactga acagtcctta gggacctctc ctttacctct 73620 gccctaattt cggttgtact tttggtgagt aatatttagg ccactcgaat tcttttctcc 73680 tttctttggc caactgcctg atggaagcag ccagccaaaa aggacccaag gacattttag 73740 cctctataag cctttttttt tttttcctgg ctttgtaaag caacctatga aggaagaagt 73800 tgcattaaat gacctcaagg gagccacgga gcatgccctc tggaatatcc ctcaccttct 73860 ccctttcttc ttaatcctac tatgccaagg accttcattg tgcatctatt ttacaagctg 73920 gagggcaacc aaaatcttcc ttaatttatg ccataatcac tgatatccag atgatgggtc 73980 tgctgcacac ctggatttct tttattttat tttatttttt gagatggaat cttgctctgt 74040 cgcccgggct ggagtgcagt ggcgctatct cagctcactg caacctctgc ctcccaggtt 74100 caagtgattc tcctgcctca gcctcccaaa tagctgggac tacaggcacg tgccaccatg 74160 cccggctaat ttttgtattt ttagtagaga cggagtttca ccgtgttagc caggatgatc 74220 ctgatctcct gacctcgtga tccacccacc tcggcctccc aaagtgctga gattacaggc 74280 atgagccacc gcgcctggcc acacctggaa ttcttttttg gctgatggca ttgttgcctt 74340 taaggcggtg tctggaaaat gagaattaca aacataacct cattatgcta ttagaaaaat 74400 gaccatcata ttcacaactg ccttcttgac attccaagca acccagagga aaatatatca 74460 agctgagaag gattctgttt ttattacttg aatattatct gccaggttag acatgtgaga 74520 acattgcttt aattatacat aagagatttc taaactggag aacaggaaac aggtagtggt 74580 cataaatgaa acaataccca gaaagagaag gcactggaaa atatttctca ttaatctact 74640 ttaaaatatt tcttttctag ttcatgaaca ttttgcatca cctgaaatat tttccttcgt 74700 acttcattta gcatctttca tattttgcct ttatttattt atttatttgg atttcagttt 74760 aagtattttt aacaggatgt ctgctatgtg gtgtttttaa tagggtgtct gttaagtttt 74820 agttctttgc ccaaagttac ctggttagtg agaataccaa gatgggtgcc caggtctctg 74880 agctccaaag ctatgcattt ccttatagtg tttagcagcc ctggcatctg ctataatgga 74940 gcctaaaata tatgcattct ctccatgtct gtgttgtctt ggtttatctt tgtaataaaa 75000 cagaccatta gaaagttgtg ctctaggacc aaatcgtctt ggctcttctt aacattgcca 75060 tcagcgtaca ctgagggcat tcaaaagaac actctctgtg aggctaaata ttgtatctac 75120 tgtggggata ttgttagagc cctgtttaca taatctggaa ttctctgtct tggaaaaacc 75180 cacaaatttt gctcaggagt ccagtagtag gagaagatgt tttgcaaaaa agtgctttga 75240 ttgttatctc atgtacaaaa agaaatcatg tcagtaatgg gctctggcta caaggaacca 75300 aattgtggct catttccaac aactgaaaca acccttatgg agcttatttt ggggctgatc 75360 ctgatccttg gctttgactt attttcctgc ctttatttcc ctttatcctc atgtcttcat 75420 ttatcccatt catcttatat gtgagtttat tcatctcaca tgtaaactgc ttccaaatct 75480 tttcttaagg atgtgacatt atccatatct atatatgcat acatacagat atttactgtt 75540 gaattattga ttccacagag tgtaatactt tgtatgcttc ctgatgcact aagtattttg 75600 cagggctatg tcttgttggt ccaattcatt tataagttcc ttgaggataa caactaggtg 75660 ttatattcat tcaagtcttg agagtcccca gcactaatat atgttgttcg ctttattgtt 75720 gattggagta tatccacaat ctgagaagat aaatgattcc taggttaaac atgcccttgt 75780 acaaatcatc ctttttcata ccagtgtcaa aaaatcaggg gctaggtagg ctatgaagtt 75840 tgtcaataca cgaattgcta tgttctttac tttgcaactt catgaaagag tcaccctact 75900 gcactagctg aatcatcatg ttgagcacaa ctcttaaggg aagtatggga aagctaaccc 75960 aggagtggca gagacctcct tttcctcctc tatcttaaca tgtgtacatg ctttgacttt 76020 gaagcaatgg aatgtgattg attccataag ccactttcaa aaatagtccc attacctgtt 76080 agtgctcacc ttaatcagat catataaatt atatgtggct atatatggaa acttaagaaa 76140 cagaaaagtc taccaggact gcggtgacaa aattcctgag tccccagata tgatgaactt 76200 atcattagtt tgtaattaat tgatatttca acaagaagct ttttgaaacg tggttaagag 76260 gaagaataaa agctggccaa actttgtcct ttggtttgat aaattctgag aatgtagcta 76320 taattctatg caaaagaagc agactaagtt acattatata ccctggtgat tatatgtttc 76380 ttcacagtgc tgtttaacat ttacatacaa tactgtaaac ctcaaagatg tcactcactt 76440 atgtaattac ctcacagtta tataaatgaa aaacctgaca tttaataagt gacactagca 76500 tatctttata taaagtagtg ttacatttaa catccctggg gactaggtat atcgtgtata 76560 ccatgcggat ggatgttctg gatgaatgaa acttaacttt ggaaacattg cactttgaaa 76620 gaatttttaa aatttttgat aaagactctc taatacaaat cgcaccattc catgactttt 76680 taaacagagg atttgataag cctgttccca atgacttgtc atggttgtga atgctcactg 76740 ttggacccta ggttacagag tggtttcttt agcggttcct gaagtctagg cctctgactt 76800 cctgtactga gtgactctgg attgagctgt tcaagaagca gaggaccagc ctgttttgct 76860 ttctgtctac cccttctgct gacagctatc atgttcattt cccaactgct gtgctattcg 76920 ttcactttac acctaaacat gtgaacgttg ggcaggaccg aggaggccct gcttccatgg 76980 agattaagga tgtcagcaga atgacagcca ctaaactcca cccctacctc tgctttactt 77040 ccaattttac ttccctttac tcccattccc aatttatgaa gttcccaaaa tctggcccca 77100 agacaatgaa agcttatttt gtacaattta attttcagtc tatatgcact caagttttga 77160 accgcttact ctaagaattt tgcacaatcc aaatccatta atgcaggtta acatattaca 77220 aaaggttaca tgaatatagg aatgatagta tgggatggag ttgatcaggg aagacttcct 77280 gaaggaggcg ccttttagaa tggtttctca atgcattgat ggatatttta ggtaaggtat 77340 aatgctatat gccttgttgc taggaccatg aactcttcag atattggctc tgctgcttat 77400 ttgctgtgtg acatttggaa agttacttaa cttttctacc tcagtttcct cattggtaaa 77460 atgaggatta taataagttc tgcttcattg agttgttgtg aagattaaat gagttcatgc 77520 atgtaaaact cttttttttt tttttttttt gagttggagt ctcactctgt cacccaggct 77580 ggagtgcaat ggagtggtct cggctcactg caacctctgc ttcccaggtt caagcaattc 77640 tcctgcctca gcctcccaag tagctgggat tacaggcaca tgccaccacg ctgggctaat 77700 tttttgtatt tttggtagag aggggatttc accatgttgg ccaggccggt ctcaaactcc 77760 tgacctgatc cacccgcctt ggcctcccaa agtgctgtaa ttacggatgt gagccaccgt 77820 gcctggcctg catgtaaagc ttttaggaca gtgcctgaga gtacaatgta agggtttccc 77880 aatagtggta gtagaagtaa caagtcataa gaaagatgcc tacagcaaag aggcaatgct 77940 taccaaagaa ctaggatgta ataagagctg aagttgacat gggaaaggac atttaaagaa 78000 aaacttctcc atctttttca ttatatggct catatttaaa aaataatatt tacatgtcac 78060 agcagtatca acaaagcggg ttgctcgcag tctgaggcaa ctgccctcag tttctggctg 78120 ctgcaggcca acctaggcta gaggagaagg aggcatacgg ataatctatt cccagcatat 78180 actgattagg gagatctggt ttagtgaaga ttttcgaaga gaagtctagg gaatttggaa 78240 gaggtgattg tccaaaggaa cagtgtgacc aaaacagata gttgtagtaa ctgtatatga 78300 taaaacagaa caagagggag aagtatggag atggtgtagg tccagattct gggggactat 78360 tgggcgtgac gtacatggga gatgaaatga atgaaaactg gggtttggtg ggaatagaaa 78420 agagagagtc cagatctggc aaaaggaggt tagggggagg tcctttgtgc tgcattggag 78480 aaacatggaa aggggccagc atagctcagt tatccaagga agtgttgata gataggactt 78540 tgtattatgg aacagcagca gcacaattag aaagcacatt ggaatcaccc ccagttatct 78600 ctgggcaggg aagaacttct ggttataaat ctattgagta ttgcaacaat tgactagggc 78660 gttttactgg ctcttagttc tcttgtacag tagtgttttt agtgcttgtt taatcattgt 78720 taatgtgaaa tcattttttc ttggactttg tagcagttta ttatagaggt tgcagataat 78780 catcagtgtt ctttatgaaa acagtaaagg attaatgcag ttgtgtgtct gtcctgccca 78840 gagcaggttc tcattaagat atggtaagtt gattttgatt tgtttgggtt ttaatttttc 78900 tctcccctct tcagaacaaa cttctataaa tgtcatcatt gttacaaaaa gagatggaaa 78960 ttcatcttta gggatttttt tttctttttg ccagaaagaa aaaaagaagg aataatagct 79020 ggacttaatt tgtaatgatt ctgaagcatc ttcaaaatca ttttctttcc ttttctattt 79080 attttttttg agacagagtc tcactccgtc acccaggctg gagcgcagtg gcgcgatctc 79140 ggctcactgc aacctccgcc ttccgggttc aagcaattct cctgtctcag cctcccgagt 79200 agctggaatt acaggcacgt gccactatgt ctggctaatt tttgtatttt tagtagagat 79260 ggaatttcac catgttggcc aggctggtct cgaattcccg acctcaagta gtctgcctgc 79320 ctcggcctcc caaaatgctg gcattacagg cgtgaaccac catgcctggc ctttttttac 79380 ttttttgaga cagggttttg ctctgttgcg cagactgagt gcagtggcat ggtcatggct 79440 tactgcaatc tttacctgct gggctcaagt gatcctccag cctcagcctc ctgagtagct 79500 tgaaccatat gcgtgtgcca ccatgcctgg ctttttattt tatttttttg tagagatagg 79560 atcttactat gttgcccagg ttggtcttga attcctggat gcaagtgatc ctcctatctc 79620 agcctcccaa attgttggga ttacaggcat gtgggccacc ttgcccagcc tcattttttt 79680 ccctacatta tactttgttc caagagcatt ctaacaggaa acactgagag agaaaaaaaa 79740 agtgattcta caagttaaaa cctgcttcag cacatccttc tctgaccccc taggaagcct 79800 ccccaagaaa tggaatggta taaactactc ccgttttcct tgtgcatatg gcattataat 79860 aatggattca cacttctgtc tcctctcatt ggagtgtgag tttcatgaag gcagggattg 79920 tattttaata atctgttttc cctcaagttt ctaacacaag acctgacaca ccaaaattaa 79980 cgatcagaaa taagaaatta gttcatatct acttaaaact accagtccat attgtagaat 80040 gttttcttta aaaatctctt tcttaaagtt taatcactgg ccaggctccg ggggtcatac 80100 ccatagtccc agcactttgg aacaccaagg caggaggata ccttgagtct aggagttcaa 80160 aaccagtctg ggcaacatag tgagaactcg tctctacaaa aaagaaaaaa aattagccgg 80220 catggtggtg agttctggtg gtcctagcta ctcaagaggc tgagatggga gaattgcttg 80280 agcccaggag gtcaaggatc tatgacgtca attttaaaaa gcctctgcaa taaggaaagt 80340 aaaataacag ctcacttgct ggactattaa aagggaaatg ggagggggcc gcaaaaaggt 80400 tttgataggc taaatgtggg cttgacaaag atctacacat ttttcttcta attgttggcc 80460 agattcactc ttcttttttt ttttgagaca gagtcttgct gtgtggccca ggctggaggg 80520 cagtggtgcc atctcggctc attgcaacct ctgcctcctg ggttccagtg attctcctgc 80580 ctcagcctcc taaatagctg ggattacagg cacccgccac catgcccacc taattttttg 80640 tatttttagt agagacgggg tttcactatg ttggccaggc tggtctcgaa ctcctgacct 80700 tgtgatctgc ctgccttggc ctcccaaagt gctgggatta caggcgtgag ccaccatgcc 80760 cggcctagat tcactcttct tatgaaaaag tacaagtttc taatgattaa ctttctgggt 80820 tatgggaagt tgtgcttcat aacaatatgg gacttgtatt cctttacact ctcatctata 80880 atatcaatat aaatagtttc tctgataagt aactaggttt ctgagataag cccttccttt 80940 tattgtagct gataacacac gattatatga ggtggtattg ctaaccacta gtgagaggtt 81000 ttgctatata atgtggaact taaacttctt tggtcttctt cccagaactg cctagatgcc 81060 actctaaatt gtttattgac agcattaata cctggagaat ttgcttaaaa gaagtagatt 81120 atttttctcc ccttcctttt tctacccaca cccccataac tctgtttttc ttaaaaaaca 81180 aaaaatcttc aaaattgtca acattgctca attgttgaga acaagggaac aagccaggca 81240 tcacatttac cctatttttt ttattcatag agctgcgtaa aaactatgtt atccaaagca 81300 ccatgaagct gcacactcac caatttcaag ataatataaa ataccacata atcaattatg 81360 gaaaataatg aaatggaatg ttggcataga aaacctcctc ggagagtatt aaaacaagga 81420 atcaattgct cgagtggcgg gggcggcgtt gggtgttaaa attaacaatc agtcaagtct 81480 ttaccaaggg ccagctgtgg gtgcagacct gcagggcacg tgtgagaagg gtcagatgca 81540 agttgctgag gtagtcactg ccctgtaaag attgtcatta attctacaaa caaacaatga 81600 aagagttgtt tgcttatgtt gtgggctaga tgcacaagat acacagaaaa ctgcagaagt 81660 gaaagtaatt cagtcatttg ttccttcatt tagcaagcat ttattaagtg gctttttttt 81720 tttttgccag gcaccaggga agacacttgg gagctgtagc ttcagaatcc gtccctgccc 81780 tcagggaagg cagaacaata agcaaacaat cataatactt tgcgaaagca gggagattat 81840 aggagatgcc gtgttagaca caaaggaaga caggataatg tgaacagcac agaatacaaa 81900 acaaaaatga agtactaatt acagaaaaca gacaggctca atttcaccta ttcctgcaat 81960 ttttagagaa gcagaggaac agaggatatg cagattttga agtgtgtcct cagcatccta 82020 aaagaaaaga aatctaggaa aagtcagact gttttttgct tgttttgaga cagagtcttg 82080 ttctgtcacc caggctgaag tgcagtgaca cgatctcggc tcactgcaac ctctgccctc 82140 tgggttcaag caattctcct gtctcagcct cccgagtagc tgggattaca ggcgcctgcc 82200 accagacctg gctagttttt taagagacgg ggtttcacca tgttggccag actggtcttg 82260 aattcctggc ctcaagggat ccgccagcct cggcctccca aagtgctggg attacaggca 82320 taagacatgg cacccggcct cagattgttg tcttacaatt ttagtatggc ttaattgtgg 82380 caaggtcttg ttaccgtaac tatttctgtc aagttatata tgaaggacag gaaccatcaa 82440 atgcaaatga agaggaagac cccttgatga gatggctcta gaagacatac gtgtgtgtgt 82500 gtgtgtgtgt gtgtgtgtgt gtgtcagggt cttgctctgt cacccagcct ggaatgcagt 82560 ggcacagtca tgtcttactt cagcctcaac ctcctgggtt caagcagtcc tcccacctca 82620 gcctccggag tagcaggtgt gtgccaccac acttagctaa tttttacatt tttttgtaat 82680 ctccctatgt tgcccagtct ggtcttgaac tcctgcactc aagtgatcct cccacctcgg 82740 cctcccaaag tgttgggatt atggctgtga gccaccacac ctggctgaca tacttctctt 82800 aattttcacc caccttttct ccttctgttc atggccagaa gatagtctca gttcttccat 82860 ttttccacct gcaaaatggg aataataaat tttcttgtat aaataggttc ttaagctgga 82920 atccttttta ggtgtccata aatagacttt ggggattcta cagtccccca cccacttaga 82980 aatttgatgc aacattaaca tgtatggtaa ttgtttctgg ggagccaatt tcaaagtaaa 83040 gtattttggg cttccctgaa ataagtgcta aataaacaac taatacttca catcacagaa 83100 caacataaca aaaccaaatt accatcatag actaataaat ctgaaataag atgctgatag 83160 tgtatgagaa tataataaaa cccagagaga gcaaagtaca cctggctttg aaatcactcc 83220 ttagcacctg agaggatcag ttcctggaat ctgctgtgta tgcaatgaca tgcatattgc 83280 taggacgtta ggccacagct ccttgggtca gctgtgggca gggaacattt gggcagatct 83340 gcataagctg ctgcccacca cctggattgt aaaaccacat gccattctgg agactttcct 83400 tcaaagaaaa atgtgaactc tcactgtcca ctaaaccact aaatactgtt tgggtgaaca 83460 ttctcccgca ccagaatcat tttcaaaaag gcagtgactg cgtttatctt gtccaccctt 83520 atatgctagg gcctggcact tataaccacc aaagaattgg ctctcaacaa tagctattta 83580 cttaatgaat gtaactgttt tggtcagaac atactggttt gaaacatttc tgatggagat 83640 gtgctggggg atgccttttc ctgatcacag agcttgatta tagcttcaat ttctgtaagt 83700 aatttctttt tctcttctaa acagcactta catgatcctc cagttgggag ccttctgtta 83760 gttgttattt ctgcatttgt gtgttgcttt acacttcaca aagggctttc ccatccatta 83820 tctcattgca tcttcacaag acttgcccca tatattttta gccgagaaaa tataaggctg 83880 gagaattaag tagcttggcc aagctctcat agctagaaag tgtggaactg tgcctcaaat 83940 ccttgttttt gctctgtgtt tggtggtttc ttgagctcac tgtgtcctga aattgtggaa 84000 ataaagttag ccagaaactc ttatcactac taatatatca gtgacagcta ttcagagtct 84060 tatggaatgg ccacataaaa atgaatttga taaagtgaat taaatgtatt tgttttataa 84120 aattatagag cctcttgata taatttggag acagcctaga ttgtgagagg gagaatgaga 84180 attcttattt tgagatggaa tcttgctctg tcacccaggc tggagtgcag tggcatgatc 84240 tctgctcact gcaatctctg cctcccggat tcaagtgatt ctcctgcctc agcctcccaa 84300 gtagctggga ttacaggtgt gcacaacgat gcccagctaa tttttgtatt tttagtagag 84360 acagggtttc accatgttgg ccaggatggt ctcaaactcc tgacctcagg tcatctgccc 84420 gcctcagcct cccaaagtgc taggattaca ggcatgagcc attgtgccta gccaataagt 84480 ctttagacat acccctgaac ctctctgaca cccctgtttt ctcatctgaa aaaatggata 84540 ccagttctgc taacttcaaa ggcatgtttt gcatgtcaaa tctaaaatac acaaaactct 84600 taaaaatatt acacaacata taaatggcag ttgctttttc aataatgtat agtgtatgtc 84660 taaatatggc cattgcattt gggtacacca aggtttttgt ccggtaaaca tcacaaaaca 84720 aaaagtaaac tgatacaaat agctatagaa atggataaat atgctgtcca tatttaaata 84780 cgaggactgg acatgagaca gatgtgcatt tgtcattgaa gaatgcagtt ccctggcggg 84840 gaaggtggaa cgtgcataag atccccatta taatgtagca cttttcattg taatcctcat 84900 agcaaccttg tcaggaagat acttactgtt cttgggcccg tttttcagat cagaaaactg 84960 aagtttagag agtttgtggc aaaattgtcc aaattataaa agaaattcca gttagcaccg 85020 acatcatgct tggtgagtgt tctcttcagt ccagcacaat cggactttca gttaacactg 85080 gttacaaaac gggctgtgtg tctttgtctc caaaagtcct atgggctgta atgctaattt 85140 tcttttatat gaattctttt ggcttggcag tttgctaata tctgtgtact atttcagctt 85200 cactttaatg tactgtattc acttttagat acataagcat aggcaatctg gggtcattct 85260 aatggagcct actcaggaca acctgaggca cctggaccta actctaatag ctctattaat 85320 gttaggtaga ccagtttaat ggagtgcatt ctcctagcag ttcattgatt ataaatactt 85380 agcttaagta cctacgtgtg tcctaaaaaa actatttgtc cgaatgaaaa tcctgatttt 85440 caggagcagt gatatgaatt ctgggcacct gtgcttcagt gaccatgggt ggagactttc 85500 ttgtttatat gtagtcctct tatgttgaaa attacacaaa aacaaaaaag tagtgaataa 85560 cagtgtcatt ttttgttttt tttgtttgtt tgtttctatt tcttttgcag gttgatgacc 85620 aaatgaagct gcttcagaac tgctggagtg agctcttaat cctcgaccac atttaccgac 85680 aagtggtaca tggaaaggaa ggatccatct tcctggttac tgggcaacaa gtgagtgtag 85740 agaccaaaaa aaaaaaaaaa gcatcttttt attaagcatg ttcagaatgg ccggaattta 85800 actaggtcag aagcactctt gtgctttgaa agggagagat tggctgccaa taatttagaa 85860 aagatgactt ggtgcactct gttcctgctc tgattattat agttaaactt gtaaaagcaa 85920 acataatcat gaacattctg ctgcttccag tctgctggga ctgaaagtcc tgcttacaag 85980 ggtccgaaga actggtaaat gaaacgtaat gattagtacc caggttttct ttttcctcga 86040 gcttctgctt taacccaaga cacttgtttg tcagctgttt taaaacctta taacttgtgg 86100 agtccttact attttggaaa aatattggtg aacgagatgg atttggatgt catgaataat 86160 tgaaatagtt ggtataaagg caaatgagaa gggaggggaa tttcagtttt caagatccag 86220 tcattcaaat gaaagataga gagaataaaa ttactgttag gtcctacacc tttctgaaca 86280 gatgtttgtt cgatcaacaa aaatttattg agcatcctac tctgtgctag ttactttttg 86340 ggggctttgg tgtatattag tgaacaaaat aaaaaggttc ctgcccctgc ggaacttaat 86400 gttgtagcag ggagaagctg acattaaaca ataatcctaa gaaacaagcc tgtaatatgt 86460 taaaggtcaa agtgctactg aataaaagaa aaaaaaaaaa aggaaagaac caatgaaaag 86520 aaaatcaaca ctcatccaca gacatgtgtt gcagtgtgac ccataagttg cactgtgaaa 86580 taggaatggt tggtttggct ttattggaaa tgtaacattt gagcaaagtc ttaaaggagg 86640 agagacagct ttgtgaatgt ctttggagag agtctactta atagacctaa ctgcaacttt 86700 acaggaattt aggcaagtct ctccagtttc ttaaccctcc gttctacaac tgatgtgcta 86760 tttaaataaa tgtgtgggac acagtgattc cttcaatcct ttgggtcata cctattcagg 86820 gtcccactgc attgttcagc aatggtgact tcagtactcg gcaccatgat cttttatgtt 86880 cagccataaa tgtttatgtg ctgtgaaacc acagcaatgc tatttggaaa tgaagggctg 86940 tctccacatc atttgctgta ttattaataa atcaaaattt cccaatcaaa ttaaaagcaa 87000 gcactatttc agagtttttg caaattgggt caattcaagc atctccatca ctatctggtc 87060 cttgctatct gcacctctca ggagaaaagc gttgcagagg agaaaataaa gtctcaatgg 87120 gtttgacttc ctgtgctttc aaattttttt tggcattttc attctgggac ccaagtcttt 87180 ggagaaaatg tacccatttt cagagtctaa tcattgggtg tgcctcccac cttcaccgaa 87240 ctaggagctg cattggaagt acaagactgg gcccactaat taatttgatt tcatttcctt 87300 ctgagtttca gaaatgaaat gggtttgtgc cgttcttttt ctcaaagcac ttccattcct 87360 gctctttaga aatatttctt atttcacatt tcattttgcc ttaagtgctg cccgtgggtg 87420 agggtaatta ctatttaaaa aatagagaaa agtgcatttc ttgctgtctg attttcaaaa 87480 ccaagaacaa tcaaggaatg gatggtatta tagttttttg gatcaattac tggtgctttg 87540 tgttttgtca tcagaactga atgaggaact ccatggtgga gaaatagtta tttccttata 87600 tgtttcctgc agcctggatt cttccagctc ccctccccac tctttaaata tgtttcctgc 87660 agcctggatt cttccagctc ccctccccac cctttaaagt gtgccacagg tctgtcagaa 87720 cccctccctt cacttttttc atccagtcca gtggctaccc tagtaatgat taattgtaat 87780 cagacattct catttatggc aattatggta gacatgttta ttttcttttg cggaatatct 87840 agacaaaacg ttttgaattt atctctgtgc ttcttgcgtt tcataggatg gaagcaaaag 87900 tgctgcaaag gaagacttca aaagcctgta acctctctat cagaatgaga cagatatctt 87960 aaagcagggt catatacatg tacttctttt atatcctcac agtacctagc acaaagctga 88020 atatgttggg cacatgatac atattacctg attgaactaa atgagaacta ttgtatctct 88080 cctggttgct tgattaaaac aaattaagta taattttttt gagaattata aatacttccc 88140 tgagtgtaaa aatgggaaaa ttagattttt gctacaacaa cattactttg tgtacacaaa 88200 ttttaagaag gtagttaaaa caatgatgag tggaaggaaa ggaatatatt aagtataaga 88260 gtaaagcaat atgctagagg aaaagaggat ttataaaaaa gaaaagaggc cgggcacagt 88320 ggctcacgcc tgtaatccca gcgctttggg aggctgaggc gggtgggtca cttgaggtca 88380 ggggttcgag accagcctgg cgaacatggt gaagccccat ctccactaaa aatacaaaaa 88440 aattagcctg gcatggtggc atgcgtctgt ggtcccagct acttgagagg ctgaggcagg 88500 agaatcgctt gaacccggga ggcagaggct acagtgagcc aagatcgtgc cactgcactc 88560 cagccttggc aacagagcaa gacgccatct caaaaaaaat aatagaaaag aggtggaagc 88620 tagaagatat atatatatat atacacacac acacatacac acaaatatat ctacatatat 88680 acatatatat acacatatat atacacacac atatatatga tatgaaagtt gaaggaggca 88740 gaaaaaaaag aaaaaaagaa ctgcttcctg ttatgtttat aatccaataa caattgagct 88800 gtggttagag tatattttct tcactagtgc agaccatgtg ctctctggtg tgtgtgtgta 88860 aaattcacac atacaggtgt aatttagaat tggaacaacc tgttttcgtg tctccattcc 88920 aaaacttcct ggctgtgtca tatttagcaa gtcgctttac cttttgaggt tcagtgtcct 88980 cacctgtcca gtggcaacta tgatgttatc taccagagag aattgcagta ggaattacag 89040 gaagtattct gtgaaatgct gacacaaaaa ttagaagtca tcaaaactag gccagcgcaa 89100 gggtgacatt tatggagtca acaaccccac gaagaaagga ctattatccc tctttggcag 89160 atgaggaacc aaggcaaaga aagatgaagt ggttgattca aggtcaagac ccatctagta 89220 agtggcagaa cagatggtca gatcgaggcc aactagtgct agagtttgtg ttctttacca 89280 acatgccata ccgtttatct gattaactca cagatgctgc agagcttgcc ttcacgccgg 89340 catttaatat ggtcttcatg tgtaattcca gtgcatgaca gactctatgg aaattccaag 89400 caaaacaaat tcatttcctt ttttattgag actaaatgga tatgcttttt ttgtggttta 89460 gttagttagt agtttgtttt tgggggaatt ttctatatgg cattgtaagc acattgttac 89520 agtagattta agttattcac aagcaatttt aatgtgattg ttgcttagtg ttatgaaatt 89580 attttaatat taagaaaaaa ctaaaactat gaaaaaatca ctcataatgc caccacttga 89640 atcaactttt tgttgaattc tcttccaatc tttgggggaa aacatgtatc ttaaaagagg 89700 atttttctca tttttctaaa taaaataact cgcctgcccc agagacatat tgacctgcta 89760 tcatggattt gtgtggaatg tgaactttca aacactgcta gaagtgtgtt tccatgaagc 89820 actgtattga ggccatgttg ttgatatcat gggaaaaagt aaatggtatt accccaatac 89880 agcatgcaaa attcccctaa aggcagcttg gtactcactt gtaggagata aatacatttt 89940 ttaatttagt taaaacaaat gcttctgatg gcctgataaa tgaagggaaa tcaaagatgt 90000 aaggggaaaa acattagaca cagctctgca gccaatagtg ataagaggca taattcatcc 90060 acctaattaa tgactgccct ttgcatagtg cttttcactg tgtactttca caggtaagcc 90120 ccattacaca gggtcagaga aagtgcgggg aaatttcaga ggaggaagtg caaggagaat 90180 aagatgggtg ttctaagctg tccagatgat tcagcttcta taaggaagtg ccttacccct 90240 aaagtgagga tatttgattg tactctcctt tgtaagttga ggaaaacacc attgcttaaa 90300 atccttctag gtcagaggaa cagtgacagg caattactag atgaaacttt aactaaactc 90360 gccacctttt tcagcctcag ccagaagaaa tacaattcac tcattataga tttccaggtt 90420 tacttacagt attttctcaa ctgccctgtt gagaaaatga ttacttctga aacaaatgaa 90480 aatgtttata ctgagtattt tgagattggc aaataggaat attaaatatg cctcagtcca 90540 caatatcagg aatgaagtcc caacacaaag ggaacaccag acagtgattt tgtttcacct 90600 tgaaagcatg tatgtcatgt ctacacattg ctttatagtg accctttgga cagacagagg 90660 aatgcaagac cccaggtgtt ccgtagccca atcttctggc tttttcttac taaacacagc 90720 tcactgtaaa taatgtggtg aatttgtcat agcagagaaa aaagaaaaag actagcctgg 90780 attttaaaaa atgagtgact atccaggaaa ttgctccttg gagcttgaaa agagaagaaa 90840 tataaaatag cacagccttt ctcttaagcc cagtggctca caagtttgct taataaatgt 90900 ttgcagaatt gaactatgtc tgttcatagt tcattcagaa ctagagaaac caaaatagcc 90960 ccactgcaaa gagcagccca ggacaccagt acattgtata ttgaaatgag gattcagtgt 91020 ttcacttaac cctgtaagtt agctattatg ttttaattgc gtctttgaat caggcatcta 91080 cataaatgta tattaaatag ccttgttaag caaaaaggaa attatgatta tcagtaatat 91140 taagcacttc aaatgttcta tatagtcgca acttagttat gaaaagaatt atttcctatc 91200 caatatttta aaaactacac acgcacatat gcacacatat atctatgtat gtataaaata 91260 ataatgtact ttgaagtggg gtcaggtttt agtatttgca tattgttgct aattaacagc 91320 cactgtaaca tcatcctaag ggaaaggtct actggcaact tattatcttc tattattgtg 91380 tatcatatta aaatgacagg catcttataa tatacaagtc atcaaaattt cagtgattag 91440 aattaaaagc aatttaggta aaactgtttt ctactttttc atgatgagtg aaatttatct 91500 aaaggggaca tcagtttaga gtattgcttc aatatctccc ttgaatttaa tgacacaaag 91560 attacatgta agagagcaaa aaattaattt tactaagtac ataaaagaca aggccaactg 91620 ctcctgaaat gagcacaaac tctgcattca acaatgaaaa tataattatg tttgtaataa 91680 aatgtaagga agttggagat ctgaatgttg tttcaagaat aaatcaccta tccttcttta 91740 gagctgtgca atttgataaa tatccttgaa agaaatgttt tctaagcccc catttaataa 91800 gcatgtttga gctttcaaat tagcatgtaa ataaatgtat agttataaat ttgttggtaa 91860 accaattgat tttttgaggt ccatctcact aaaggtctct cactaaatat ataatcctat 91920 gaaacagatt cctttccgtt atagtgtact acattttcac atatgaaatt cttgtatttg 91980 aacttattat tatacacctg ttagaactat acacaacaat atttaattaa ctccatctta 92040 ataatggaaa attaatacca acatatttgt gtttcatttt agtatggtct tcctgattca 92100 ggccttaact agtgattttt ttttcttttc tttttttttt gagagaagtc ttgctcttgt 92160 cccccaggct ggagtgcaat ggcgcaatct cggctcactg caacctccgc ctcctgggtt 92220 caaacgattc tccagcctca gcctcccaag tagctgggat tacaggcact tgccaccacg 92280 cctggctaat ttttgtactt ttagtagaga tggggtttca ccatgttggc caggctggtc 92340 tcgaactccc gacctcaggt gatccacccg tctcggcctc ccaaagtgct gggattagag 92400 gcatgagccg ccgcacctcg cctttttctt tttttttttt tttttgagac agtctcactc 92460 tgttgcccag gttggagtgc agtggtgcaa tctcagttca ccgcaacatc tgcctcctgg 92520 gttcaagcga ttctcctgcc tcagcctcct gagtagctgg gattacaggc atgtaccacc 92580 acgcccagct aatttctgta tttttagcac agatggggtt tcaccatgtt ggccaggctg 92640 gtcttgaagt cccgacctca ggtgatccac ccacctcggc ctcccaaagc actgggatta 92700 caggagtgag ccaccgcacc tggatcttaa ctagtggtat ttactacaat atactttgta 92760 tatattaagc tacagctaca gcgcattccg ttgattccaa gcttaaattg ttaatcttgt 92820 cccatctatg attcttgata atcatagaag tgagaggtac cttattatca tcacctaact 92880 taactgcctt acttaaagat aaggacacca agggatggag atttatacgt acttgtccaa 92940 ggctcttcgt ttgtaagagg cagcattggc tcgggtctct tacctagtct ctggcttttg 93000 ccaccactgt tgtaccatca ggccttcctg ctctcattca ctcatctatc ccattagtct 93060 cagtaaaatt tgtattatta ttatctgaag tagttgacta tgtgcagttt ttaaagaatt 93120 tatagcatag gcaccttttt aaagtaagga ctttccttga agtagaaagt tcccctgtaa 93180 gagaactggc aaaatgatag ttgagacgtc actttgtgtg ctctgcaaat aatcccaatg 93240 tgccccacag agttcaacag tgtgtcctgc ctccttccag ctcagggttc aggttgccca 93300 ggtactgacc cttctttcac acattctgaa acagaaacca caggagttct tacaacactt 93360 gatgtttaaa tttagtgcgt agatgccagc acctggctaa agcaggtaga cagtgctgta 93420 catgatgcaa gagctttcct ctaacacaca ttaactgtgg ctttttcatg catagttgac 93480 tctatataaa ctgattgaca cctttggggg tcatctttcc tctgactcat aatttttctc 93540 actcttgaaa aaggtttctg tacacccagt attctctagt taaagctgaa aattcaactc 93600 atcatattta cacaataaaa aaaatccatt ctgccttgtt tttaattgca aattctactc 93660 aagggactag ttctcctgct taggaggcag ccctgtgcct tctcctagag aagcaagtgc 93720 agtcaattat ggtaatgaaa tgtcaataaa tataaaaatt taatacagtc tgctctgggt 93780 gagtggcaga tgaggacttg cctcccagac aaatttgctg ctgctgcaaa tattaaatgc 93840 acctaaaaga gtatctggtt gcctgagagc tctccagtaa aaaaaggatg ggagcgtcag 93900 gtaccaactg ggctttccca ttatgctgta atcgcagcag caaagccagt gctatcactg 93960 acagccatcc caacatctta acttgttata aattgaactt cttatgtccc catgaataat 94020 ctaagattgg tgcctagcaa cacttttttt tttgagacgg agtctggctt cttcccccag 94080 gctggagtgc aatggcacga tcttggctca ctgcaacctc cgcctcccag gttcaagcaa 94140 ttctcctgcc tcagcctccc cagtagctgg gattacaggc acatgccacc acgcccagcc 94200 aatttttgta tttttagtag agatggggtt tggccttgaa ctcctggcct caagcgatcc 94260 gcccacctcg gcctcccaaa gtgctgggat tacaggcatg agccaccgtg cccggccagc 94320 actttttttt ttttaatgaa aagggaaata agccttttct ttttttgctt ccagacaacg 94380 gaattattct cctaaataaa gttattgctg tctttagaga gaaacacatt aatctgatgt 94440 aatctaatgt aatcatctga gaatagcagt tttatgtcat gctttttagg aaacagaaaa 94500 ctaaagaata atttatttgt atttatttta aatttttaaa ttaacacttc tgctgttcta 94560 taaagaataa tttaaatgtg attctttcat catccacaaa catccaatct tgaactatga 94620 ttactttaaa atgtagtctc ataatacaag tagaaatata tctgccttta ttttcctcat 94680 gcactagtta atattgtata tacatagaac actctcctgg attcactttt catggacagt 94740 atgtttttct ttcaccttat tcatgagagt taaaattttt tatcttatgt gatgatgtaa 94800 tttcataata taaaaaaggc atatatactt gaaaaattta ggtagccaaa acctctttcc 94860 tacaaagctt atcaaaagtg attatattta tcagacatag taattctgat gcattttaga 94920 atcatggaat gtgcctcaaa ctacttgcat ggggaaaatc ccttctgtta tcaatctgta 94980 ttgtggccag gcatggtggc ttgggcctgc aatcccagca ctttgggagg ccaaggccag 95040 aggatcactt cagctcagga gttcaagacc agtctggtca aatagtgaga ccccacatct 95100 ctattctatt ttaaaaacct gtattgcaat ctgattttac ccatagttct tacgactcag 95160 gtgaaataca tattgctgat tctgatagtc cttaaaactg tgattctgta ttgcaggtgg 95220 actattccat aatagcatca caagccggag ccaccctcaa caacctcatg agtcatgcac 95280 aggagttagt ggcaaaactt cgttctctcc agtttgatca acgagagttc gtatgtctga 95340 aattcttggt gctctttagt ttaggtaaga aatccttttc tcatgctgtg ctcaaccaac 95400 gattgctaaa tgatgttgaa gttcaaatat cttgtggtcc atgtatgttt ttgttctatc 95460 aatataatgc ccttcctgtc aaattatgaa atcttcaaac gtgaatatat tttcatatat 95520 atttctgcat gatgcatagc ccttcagtgg atacgttggg gaatggaaaa tgagttattc 95580 aattgactca ttcaaatgag tcctggtttt tcttccataa tatacagata agcaataacc 95640 aaataaagct atgacaaagg tttaaaacag acagcttagg aaagatgtat ggtatcaaat 95700 tttagccatc tttctcccat tggtaatttc tatgtgcctt tcgtttcaac ttgctattta 95760 cttctgtttt tattcttcta aaatatgaat cgtaattaaa aacctgtatt taaatctcta 95820 tcgggattaa ctagagaatg tttataacca gatgcaccac tatgcaagta caaaagatga 95880 cagttgtcaa ggggaaagga tgattcttta ggaaagcttt ggaaaagaaa gataactaag 95940 caagacagat tagctaaatc aaggttctca gtgagtcagt tgagaaaaat caccacagct 96000 tggaataaaa aaaggattaa ggagatggat ttttattgac ttcaaaggaa cagattttcc 96060 tgtctgtccc ttacttgatt tctgtatttt gttggcttaa taaagccaac ttaaataaac 96120 tttttgccaa gtccatttat tacttattgg cagacagctg agggaggcaa cttcccttga 96180 atgaaaaaaa tgcagaaatc agattcacca acatatgttt tttctttagt cttcagttat 96240 aagatagttg tgaattcata ttctagggaa taaaacaata aaacaaactg caaagtaaaa 96300 cagatgtgtc tactctccaa atttggtact ttatttttaa aattcttctt gacaggactg 96360 cacaactgtt gctaataaag gggtagtttg aagtaataga accagagtta atttttcatg 96420 tatagtcaac atttaaaata aaaagagcat tttcatattt tggaaaatgt gataaataca 96480 gcaaaaagaa atgttactga aaatttaaat ggacaacaga atttcatgga tgtaacgttc 96540 aaaggtttac aatgccaaga ctggatcctg tgtggtttct gtattaacca caataaaaag 96600 gaaagttctg ttcaagtaag tctgcatctt ttacccgaga acagtgttta gaatgttaaa 96660 aaggaagata gcaagcatac gcctgcttgc tgtaatcgca caaattattc tggtttatgt 96720 taagatctta gtcttttaaa ctagtgcatt tgatcactaa ttaaatggaa aatgtggtaa 96780 tatatgtata agaaactgta tagcatctta gtgataaaat atttacaggg tcatctcatt 96840 tcaatggtat tttaaattag ttgaagaaat gtattacatt tgaagatgta catattaacc 96900 atgagccatc tttagttttc agcactttta actttccttc atcatcttcc aaaattatta 96960 tattctctgc taatactata aggagggggt tgggctagat ctgagatgct ttcaactttt 97020 gaacctcaaa aattatcttc ctgaacaact gggccatgta tttaccagaa ctttagtcat 97080 acactctgat gtttaatgag cacttcgatt gtttcaggag cccagtacac cagtgaatag 97140 ctggcctaaa tgtccattaa atccatgtct atttgttgct taaggaagaa aggaaagcat 97200 ggctttcaga tcagaggcaa atagaattct ggccgagagt ctattttttt agagaagcag 97260 gagaaaagta accagtagta aaattcaagt agtttctaat ttgtgagtgg aaaaactttt 97320 tactctgtag aaacagtggc taatcaattt tttgaatttc acctttattg aggtatatag 97380 ataattaact ttaggtgcct cagctagccc caaatgctgg ttttacctgt gattaagggt 97440 gaaatcatac cagagtcact cttgaaagtt aaggccaagt cctaagctgg tacctgctgt 97500 cccagatgct cctcctgagc ctcgagtccc ctgagtctga agcctgctat atttttgtct 97560 cagcccagcc ttgagactct ttggtcctgg agaaaaatga agattctgtg gactagtcag 97620 aggccagggt ctattctgag agatgactgc agcagtattc tcctgtgaga gatgaaacag 97680 tgttttccag atagatttgg tgagagaagg tgggatgtgg tcccaagcgg gtgcagcgtt 97740 ccaagctaga agcactacca gtgtgaaagc ttaaaggcaa gagagagcaa aatgagtttg 97800 gggaactgtt agttgatgga tacggcttga gggaagcagc agatgtggct ggagacatag 97860 acaggagcct ggacatggac atgaaagcca cagatgcatt caacacatac tcattgagtg 97920 cttactatgt gtccagcact gaagaaggca ctggggctat agtggcaaga agaagtaagt 97980 gccatggctt tcattctcta gacaattagg aagtatagca gtgttcttaa ggcgacgggg 98040 atgcggtgaa taacttaagt cgatttgcct ttctggtagc agcatggaaa gtggactgga 98100 ccaagaacag tgctagaaac cctgttttca gaagttttat ttttatttta cttatttaat 98160 tttttttttt ttttgctttt attcctggca tgctgtgatt tatttttaga ggtggttttt 98220 tttttttgaa acggagtttc actcttggtg cccaggcggg agtgcaatgg catgatctca 98280 gctcaccaca acctccgcct cctgggttca agtgattctc ctgcctcagc ctcctgagta 98340 gctgggatta caggtgcctg ccaccacacc tggctaattt ttttgtattt ttagtagaga 98400 cggggtttct ccatgttagc caggctggtc tcgaactcct gacctcaggt gatccacctg 98460 ccttggcctc tcaaagtgct gggattacag gtgtgagcca ccacgcctgg cctagaggtg 98520 gttttaatac tccatgtggt tggactgaga tgaaggatac aaaccagtta taggtttcaa 98580 gccacaagat gtggcagagt tgagagggaa aagtctaggg tgtgtttggg gcttctggat 98640 gtctagctgg aatagaaaca tctacaggaa cagtaactga tcagttgatt caaagcgggt 98700 cccaatagca gtcatcactt tctaatctaa aagtcattct tcactaaagt ttgttactgc 98760 tgacacaaaa agctcatgac aggactcaaa agaaaagtac agtggactca agtccttcta 98820 gtttgctctc tgacgtttcc cccctcagat tgtatccatg agcagacatc agttgggtaa 98880 gctggtcaag aaaggaaata agtaaaaaat gccctctcag cacatttctc tgtgtataac 98940 atcatagatt ctgtaggccc aatctctgtt agttgttagt tttaatgttt tctttacatt 99000 tctagcacaa tgcttggtac atagtaggga cttacaaaat gtttactgat aaaaataaat 99060 aaatgggcca ggtatggtgg ctcacacctg taatctcacc actttggagg ccaaggtgag 99120 agaactgatt gagccccacg ggtttgagac cagcctgggc aacataggga gaccccatct 99180 ctacaaaata attagccagg tgtggtggca gacacctgtg gtttcagcta cttgggagga 99240 tgaggtggga ggatcagcca agatcgtact acttcactcc agcctgggca acggattaag 99300 atcctgtctt agaaaattaa aaaataaaaa taaacaaata gtttgaaact taaagcgaag 99360 cctttaccga agcaactcgt gataggtaat aggaggtggt ttagctaaaa gccgtattca 99420 aatacaggtt atttttcaga gaccactttt tccaaagaac tctctaataa ataactcctc 99480 aaaattaaat tatttctgtt atcagtttgc attctcccag tttatgagag gagatgttta 99540 ttcataagct ctttgggaaa gctaacgtga agaaaaatta gaaagaatat tactgactaa 99600 aaccaggtgg caaatgcatt tctgttccaa gcaaatgcaa gatgataggc tttcagccca 99660 tgttaagtaa tagtagttaa gacaatgttg tacaattctt tcttggcatt gatacaatcc 99720 tgtttccagc aaaatgaatg gagaaaatgt tatatttgtt catcatgata gctctttgct 99780 tcatactaaa cttccaaatt ttgaatgtga catttgatta tacacatccc aggtaagttt 99840 tgtcctcatg gagacaaaca ccccagggaa gatgggttat ggttgcctca gggaatgact 99900 caactggccc agacagaaaa gctactgcat gctaaatgtc ctcaccagcc tgtcacctga 99960 tcctcatctg cagagaagca acgggcataa ttcaagaaca aaactgattg aagagttgct 100020 tgtttcatcc acaggttcag ttcaggcatt ctgtagtgtc tagtcatgat ttctttatct 100080 taaaataatt aagaacatta tcttaaatta taaaaggtca tctaagcaag tactataatg 100140 tctcagaata aacagtattg tttattaata aaaaatgtga cttgaacaca agttgaaagg 100200 gattttcaaa atggatgggt aagaccttca gggcttgaaa gaactttatt ttattattta 100260 ttcttcttaa ttttagagac agggtcctgc tctgttgccc aggctggagt gtagtggcat 100320 gatcataact ttctgcagct tctaactcct aggctcaaat gatcctctcg cctcagcctc 100380 ctgagtagct ggggctacag gtcacactca ttgcctggct aattttttaa tttttttata 100440 gagacagggt ctcactatgt tgcccaggct ggtctcaaac tcctggcctc aagcaatcct 100500 ccctccttgg cctctccaag tgctgggatt gcagccatga gtcacaacat ctggccctcc 100560 cttgaaagac ctttaaaatc ataatttgga aggaaaaaaa cagtatttct aaggcagagc 100620 agaacatttt tctctttgtt gtggctactt taaactgtat aagtctgacc ccaaacaaag 100680 ttgggggcag ggctctatgg ttgttctggt tttctctttt tattctttta ttttttctgt 100740 gctaagtgaa atgttcttgt tttcttagtg aagcaaagtt cttttatctg tcaaattaat 100800 aaactgtaag gttcatgaac acagtgtatg ttttactcct catgtactgc ctggcatata 100860 ggcttttaat aaatattgct ttcatgaatg aaagaatgcc tttcctccca acttctagat 100920 taaaaagaaa aaaataatgg gaattgaaaa taattagcta aaaaaaatgc aagcacaaaa 100980 tttgaagaaa gagagactag aaaacagatt ctatggataa ctattagagg atttggcatc 101040 ttcttttccc ctttagaaag tagggagata agtcttcaca ttatgaaggg gatttttttt 101100 ttttttttta atttttagta cagacgaggt ctcactatgt tgcccaggct gaactcctca 101160 agtgatttgc ctgcctcagc ctcccaaagt gctgggatta taggcatgag ccactctgcc 101220 tggcctatga aggggattag tataagtaat gtagagacta aactgagtcc ctcctctttg 101280 caaataaaat aataaatgaa attaattact gatgatcagc atttaggttc tatttgaagt 101340 tgtaacacta acagtgtcaa acaccaaaat gagccataga aggaagtggt ggtgatgctt 101400 ttcttcagta atgttaataa taaaatgtcc tcaggtgaat aaatcactta gtttctctct 101460 tacagaatga agagacctaa gagaacattc tcctccagtt ttgtaattaa aaaaacaaaa 101520 ctagatgatt tatccaacat tttaggttca gatccaggtc tagaactaat aaccccaaat 101580 gacagtcagt actttttctg attcagccta ctttcctctt cggagacatt ggatctcatc 101640 aatgagcata ttaaaaatac tgtgtaaaga agacctttga agacacaggt ttgaactgtg 101700 tgggtccact tctgctcaaa attttttttt caataaatac agtcagccct ctgtagctgc 101760 aggttctgtg tacaaatgca agtccaaaat acagtatcca aaaggccggg tacagtggct 101820 catgcctgta atcctagcac tttgggaggc caaggcgggt ggatcacctg aggtcaagag 101880 tttgaaacca gcctggtcaa catggtgaaa cctcgtctct actaaaaata caaaaattac 101940 ccaggtgtgg tggtgggcac ctgtaatccc agctattttg gaggctgagg caggagaatc 102000 acttcaaccc agggggcgga ggttgcagtg agctgagatt gtgccattgc actccagcct 102060 gggcttcaga gaaagactct gtctcaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaat 102120 atatatatat atatatatat ggtatccatc agatgcaaaa tccacatata cagagggctg 102180 acttttcaga tctgaaggtt tcacagggta gatggcagga cttgagtatt tgcagatttg 102240 agtataggca ggggtcctgg aactgatccc ccttgtatac caagggagga ctgtacttac 102300 taagacacta tttatttatt tatttattaa ggcaaaatga tataagaaat taggacagtc 102360 atctgaagaa tgtggacaaa aataaaagca atatctattg gtagaagcag agaaatactt 102420 cacctgaatt tccaattttt attgaatatg ctaagtaatt atatagctct taattcactc 102480 agtttctaaa taccgtcatc cctcagtata tgcagggaat cagttccagc acccctgttt 102540 ataccaaaat ctgcacacac tcaagtcccg cagtcggccc tgcagaaccc gagcatacaa 102600 aacattggtc ctccatacag gcaggtttcg tatctgtgaa tactgtgttc ttatctgtgt 102660 ttggctgaga aaagtctgca taagatgtgg actcacgcag ttcaaacctg tgttgtgcaa 102720 gggtcaactg gatattgtca gttttgtttt tctctatgtg aactctgggt ttcagagctc 102780 cagcaagctc ccagaatgca tttgcctcac agctttggta cctctttctt aaagacttcc 102840 tccttgtagc tgattgtcac ctcttaggta tgacgttttc tttggaccat tcactagaca 102900 ttaggaaagc caaatgatca tagctttcgt tatatatatg tctattttag gatgtatttt 102960 aactgcttgt gatggtaaaa ggaaaaataa taacaaaaca aatagtcatt cttttcccct 103020 ctgacagtca ctggcattaa aaatcctaaa gtagccaatt gcatctctaa gatttaggtg 103080 gacgagctcc ctggggcagg gcagggtgga gtgggggtgg tgggcaggca gagaggagtg 103140 tagtaagttt gtacattctg ttttcaagta cagccgtccg ctttcctgaa gggttcaatc 103200 ataactcggc tcttgcaata tgacactgac attgttaata gtaaataaaa tgtttactag 103260 ctgaaagatt tggataaaag tcttttagat agggaaattt atttgcagtg gttagttttc 103320 caatagtctt tagtttctgc tataggaatg tttttcttat ttgaattttg tccattattt 103380 cttctgcttt gacatttaaa gaaatatcta atgcttcttt tccctttact taagtgtgtg 103440 ccatttgtcc tctggcattc aatatcagaa cctggcagag gtttgctgtc aaagctccct 103500 atagagtggt tggtaaggca acatgcaaat agggagactg gccccatacc ccaggcccag 103560 tcaggacctc tgcccagagc ttataactcc agcacaagcc atcatatatg ggaactctgt 103620 ctcatcactt ttgagactct ctctctctct gaatatatac acacacatac atacacacac 103680 acacttcatt tgaaaatgaa ggctttataa acaagccaag aactgcagag caactactga 103740 tctcacatct cacttaagag acaacagaga tttgtaggaa tagcaaacat tcagccatta 103800 agtgaggcat acaaaaggct gctgtgttaa catagcccag aaaaccacgg cacttcaatc 103860 agaacgtctt tctccttgtc tgtttttctt taaaagagga cccttccttt ttgtccgata 103920 ggaagtacta ttctgaatct accagcaagg ctggcatgtg ctctcttata aaaggaaaag 103980 acttcaccat gcatagcctc ttcaccctaa ctgctcagtt gtttgctacc cctggcaagg 104040 atgttctaat tgtgcagtgg agggtgtgaa ctcgttgctt taactgcagt tccattagct 104100 aatcggagtc ctgatgtcag tgtgacattg tggtgtaaat catgaagggg tttttctgcc 104160 acttcctgtg gagagaaaac agttttgcag gatcacctga tgattggcca ttgtggggtt 104220 gtcttcttga aaaagaaaag ttgttctgac ctgggctgtg ctcaggatgc ctacattttg 104280 cctttgctaa gcgatgaacc ccccagaaag gaagtgtatg gggggcactg ttggagtctg 104340 agtgctccct tccctcagca cttctggaga agcctggaaa tactgtagac acagttttgg 104400 agaagagaat tcaaagggct tacaaaagga gagtactttt ttgtccactt ctctagaaga 104460 ggcacagcaa cttgttgagt ttgtgttgtg ttgtgttgtt tttctgccac caaattaggt 104520 gttcctattg tgtgggaggt gaaaaagaga gcacaaatct attaataagt aaagcaactg 104580 aaacaaaggg aaaaatgaat ccccattttg cttttttgca acattacatc cagttaataa 104640 aagaggctta caaatccaac agagatctgc ttgcaggaac taactaggaa gaagaagaag 104700 aagaagaaga agaagaagaa gaagaagaag aaaaaaaaaa tccaacagag aaatttgatc 104760 actgatttaa attgtgtttg cagtgcctaa agcaagatga acgattcatt cactgtaagt 104820 cagaaggtga cagtaccagg tgtaccattt gctatatggc aaatctacag ctgctctaga 104880 aagtgaaata gcagtgcctg ttcttatccc ttagttgact acctcatcac tggaagtgct 104940 gtaagagctt cagaagggtg gaaaactagt aaaaaatgtc caattgtgca tcaaaattta 105000 tgcttattaa ttctgaaata agcattatag tctaaacatc ataaaattct ttttgcttgg 105060 tagctgcata aaagttggtt ttgaaacagc aaaacctgat tttcctatta tgtggcaatt 105120 ctccttcctg aagctggtca caatatttgc tttattgctg gcttcctcta aatatgatta 105180 catactcacc cacacacaca ctgccactgg ctggactgca aagcctagtg aagcagaaca 105240 tttacctcac atctttaccc aagagcattg gttaaattgt tcttcatgaa gtcagataag 105300 caaaagaaat atcccagggt tcttcgtaca attagcattc attctcagtg tttacctttt 105360 catatgtaat attctaattt agaaaaacac tcactagaca cttgtcaaat aactgcacat 105420 atcttcatac taatgccttg ctgatatata tgcacctgag ggtaatgctg gcaaataagc 105480 atttcctaaa atttatgtaa tcatttgaaa ttcagaaagg attgattagc attcaagaga 105540 tgccactgtt caatatttac accatagaga tttggcagaa gcaaataatg gcatataaag 105600 ttgatgcttg tcttaattaa atgcagtata ataggtgttg tggatttttt ttttcttcca 105660 gtgagcaaag cagtttagca atgaccagat gtaattcatt ttggagttct aagtttgaac 105720 ttaatcaata tgaacttaca gccatggaag aagtgattat catttgttat ttgctggcac 105780 aagaatataa ttgcctaaat agcatttatt taagcatatt tctgaatacc ttatgcctaa 105840 aaatatttgt catattttag ctgttaatgc ttatcttgtc attttgctaa ctactgctat 105900 ttagtgagat gatttttcag agacatattg gccaggcaag ctaggaataa ccagcaagaa 105960 aaatcaagtg agaatgccat gtgctcttgg ttgatgtttc tcgctgcttt agctgtgtca 106020 accactctgt tcaaatctca gaatagagtg gctgtcttag taccagctca gaagagcgta 106080 gttggttaac gtggttagcc cagatgctgc actctagtgg actctggaca ccccagggcc 106140 tcaggtctgt tctacaatgg accaaatcag tgactcacat ctgagtcttg cattagatct 106200 tctttctagt ttactgataa aaatctgata agtcttatct tgagttgtgg ctgtgtttgg 106260 ttaagaaggt taaatttcaa acagaccaat ccaaagccag gagagaagaa caaatagaag 106320 tacaaggcct ctcatcagta ttgaaacatt aaatcacaca aaatatattg agtggccact 106380 atgcagaacc attgtactag gcaagctatg aaatgacaac atagagtctt ttttttgttt 106440 gagatggagt ctctctctct ccagctggag tgcagtggtg caattttggc tcactgcaac 106500 ctccgcctcc tgggtttgag tgattctcct gcctcagccg cctgagtagt taggattaca 106560 agtgcctgct accacccccg gctaattttt gtatttttag tagagacggg atttcaccat 106620 gttggccagg ctggtctcaa actcctgacc tcaagtgatc tgcccacctt ggcctcccaa 106680 agtgctggga ttacaggtgt gagccaatgt gcccggcaag aactggcaat atatagtctt 106740 tccaaagaga aggaaactcc tgtgatacag agctgcattt tggatcccca ggacactgtt 106800 ctgaataagg cgtggtacac caagcgaaga gtccaaaaca tgccatgcca tcagcaatgc 106860 tgcatgcatc tcttgtcttt ctttctgttc cttgttttca ctgaactaat gcacgttcca 106920 cacacatgct attctccttg attacatttt attaatcaga aagcctttgt caacccccat 106980 gttacataaa tctcacagca atcagaggct tcatgcctct tcagtttccc aactcctctg 107040 aaaggagatg atttttcaga gacatattgg ccaggcaaac taggaataac cagcaagaaa 107100 aatcaagtaa gaatgccatg tgctcttggt tgatgtttct tgctgcttta gctgtgtcaa 107160 ccactctgtt caactcctct gaaaggagtt gggaaactgc atgggatcac ctccaggagc 107220 cttagcaagg ggcactgtcc ctaacaccca catcccaagt tacccagatt ttggacagca 107280 ccaatgtggc ctcagccctg gaggaactga gtcccagaac atcagcatgg aagagaacct 107340 atgctgttgc tgaatacaaa cacgtcttat ttctgagtaa gaaaatttaa gctaatggag 107400 gttaagtgac ttgtacacag tcatgtagag tcaggatttg aactgaaatt tttgaactcc 107460 acacgcagga aaagagcaca gatatggatt tctatattac agaaatagtg cttttgcatt 107520 tgtttcaaaa ttagacttac tatttcttgg ccatcctttt caactaaatc taaaattttc 107580 attgtgaagt gtaaaagtga tttcccagaa acgtggggaa tgtacattgc cttttgctgc 107640 cttaggactc agctgtgcat gctgcatgct gggtaccctg aactttggag ggcagaatct 107700 ctcctacagt cactcacact ttgactctct ccactttact ctgggtacat ggagctctgt 107760 gccatccata aaggtcagtg tgtcctgagt ggccatgctg gactcaaatt gggcaattct 107820 gcctaatccc tcagcaggaa tgatcatatt cattttgtcc tatcttggtt atacagtcaa 107880 gcgttatata atgatgtttt ggtcactgat ggactatata tatatatata tatatacaca 107940 cacatatata tatatacaca tatatacaca catatatata tacacatata tatacacata 108000 tatatatata cacatatata cacacacaca cacacgtata tatgtacata tatacattat 108060 atatatatgg tcatatatat gatagaagac tataatggag gtgaaaaatt cctattgcct 108120 agtatttacc ctactatata ctttgaagtt attttagagc atattcttta tacctatgta 108180 tataaaagaa aacttactat aaagtagcct caggcaggtc cctctggggg tatccagaag 108240 aaggtattgt tataggagat gacagctcta tgtgtgttat tgcccctgaa gaccttccaa 108300 tgggacaaga tatggaggtg gaagacagtg atattgatga tcctgacctt gtataggctt 108360 agaggctaat gtgtgtgttt gtgtcttcat ctttaacaaa aaaagtttaa aaagtagata 108420 aataaattta aaaatagaaa aaagcttatc gaataagcat ataaagaaaa ttttcataca 108480 gctgtacaat gtatttgtgt tttaagctgt gttattacaa agagtcaaaa agcttaaaga 108540 aattgaaaag tttataaagt aacaaaggta tagtaagcta tggttaattt attactgaag 108600 aaagaaaaat attttttata aatttaatgt agcctatgtg tacactgttt ataaagtctg 108660 cagtagtcta caggaatgtc ctgtaccttc ccactcactc accactcact cactgactca 108720 cccagagcaa cttccagtcc tgcagtctcc acctatgata agtgctccat acaggtgtgc 108780 tattttttat ctcatagact gtatttttac tataccttgt tttctatgat tagatgcaca 108840 aatattcact gtgttacaac tgccttcgat attcagtaca gtgacacgct gtataggttt 108900 gtagcctagg agcaataggc tttaccacat atcccgggtg tgtagtaagt ttgtgtaagt 108960 acactctatg atgatcgcgc aacgaaatca cctatcagtg cacttctcag aatgtatcct 109020 tgtcattaag caacacatga ctgtgtatat aagaattgat agcacacctg aaataatcct 109080 ttctctgtac catttatccc aagagaaagt aattattata gtagtgttaa tactgctaac 109140 atctatgtag gaatttttaa gtgcagattt atttaatttt taatttttaa aattgtgata 109200 aaatctacat gagatttacc attttaacaa tttttaagta tgcagtttag tggcattaag 109260 tccacacaca ttgcaactgt taccaccatt tgtctctaga acttcctgtc ttccaaaatt 109320 aaaactgtgc ttatgaaaca gtaaattccc aattcaccca ctgctcagcc cctgcagccg 109380 tcattctgtt ttctgtggag aacattttat ttacaaagta ccctattctt ataacattat 109440 cctttacaca taacacaaca ttgaaagttt agtgatttta taatacaaaa tgtgactgga 109500 ctcagcatgg ctaacgtgct catgaccaca cagctaggca tctgagagag cccatgctcc 109560 aagccagggc cactgattcc agatctgctg tcgtcactca caggcaagga agtcttttga 109620 cttggggcct gaaataataa agcatgaggc caggtgcagc ggctcacgcc tgtaatccca 109680 gcactttggg aggccgaggc aggtggatca cctgaggtcg cgagttcgag accagcctag 109740 ccaacatggt gaaaccccgt ctctactaaa aatacaaaaa ttagccgggt gtggtggcat 109800 gtgcctgtaa tcccaactac ccgggaggct gagacaggag aatcgcttga acctgggagg 109860 tggaggttgc ggcaagccaa gattgcgccc ctgctctcca gcctgggcaa cagagcaaaa 109920 cttcatctcc aaaaaaaaaa aaagaagaag aagaagaaga agaatgcatg aatgaggaaa 109980 aagagaggcg ttcatgacaa gtttcttact attgaggtga tatggcctaa tggtgatgac 110040 tgcaaacttg aattcagatt cttgttctat tgtatcctta ggaacgtgta tcacctcact 110100 tttttccatc tgtaaacttg aaataataat gatctacctg aagcatgatt gtgatggtta 110160 catgcaataa ttattaggaa gaacttacca taatggctgg cacatagtat taataagtga 110220 ttattactca aaacatctgt gaaagtcata gaaatgaagg ctgcttatcg ggaaatgcct 110280 cttctcagat acaatctttg gtttacagat tctgtgaaaa agatctttct cacgtcagca 110340 ataactgata cattaattca gtaccaagcc atagtttgaa atctttgatc tactaaccaa 110400 aggcatcatt attatccttg atgttttgga atatgtcaga gtaagcagac tcaagccgct 110460 tcactttaat tcatctatca taaatcccaa aatcaagcca aggtctaata ataaacaatt 110520 aggcctcttc ctaggttggt gcaggcccta gatgatgaga aagtggaatg gctaggctca 110580 cacctgccct ctgggaatgc ctatgctagg aagctcttca cttttttctt tctttttttt 110640 ttttggagat ggaatctcac tctgtcaccc aggctggagt gcagtggtgc aatctctgct 110700 caccgcaacc tccgcttcct gggttcgggc gatttgaaca cacacaagaa agagcacaga 110760 taaggatttc acttaacatc atgcctggaa taaagttcat attaaaaaac aatactcagt 110820 atgttcgatt ataatagcta catcttattg tcctgtatga gcagagtaca ttatacctgt 110880 tgtttctaat cttcataagc aagccttcga tgaaagtatc atttgccatt cctgttttac 110940 tgtctttccc taagatcaga gaagtcaaac aactatacaa aattgctgag ctagtaagta 111000 atagaactgg gatttgcaca ctttagtcat caaagtctag gttttctcca ctattcactg 111060 ctacttttct ggttcattga ttaagtatgt agatcagaag gcactatacc agtgcttgtc 111120 atttatgatg aagctaaccc attctaaatc tgatccttct agatcctact tgaaagtaca 111180 agggctgagt aacaatcctg ccttcttaaa tgcttaataa ttccccctca tcaacatgcc 111240 atggtttcag tcagagctgc tttctattga tcggtttcaa gaagtatcac agcttttatc 111300 accacggtca gaagcactgc tgaaattata gggtatttaa tcccttatgc tggcctactt 111360 actctaagca gattttcttt tctttatctt ttttttgaga cagagcctca ctctgttacc 111420 caggctggaa tgcagtggtg tgatcctggc tcactgcagc ctcaacctcc ctggttcaag 111480 cagtccgcca gcctcagcca cccaaagtgc tgggattaca ggcatgagcc actgtgcctg 111540 gccagatttt attttattta tttatttatt tatttttgag acagagtctt gctctgttac 111600 ctaggctgga gtgtagtagc acaatctcgg ctctctgcaa cctctgtctc ccaggttcaa 111660 gcagttctcc tgcctcagcc tcccgaatag ctgatattac aggtgcacac caccacacct 111720 ggctaatttt tttttttttt ttttttatgt ttttggtaga gacgaggttt caccatgttg 111780 gccaagctgg tttcgaactc ctgacctgaa gtgatctgcc caccttggcc tcccaaagtg 111840 ctgggattac aggcgtgagc caccacacct ggcccagatt ttacttttaa tatgaagaaa 111900 catctgctgt ctaaattcct atcctcttac aaatatttac tgtgaacaga atttgataat 111960 tgattgaaaa tcattaccag attattagcc tagattatta gcagattctc cctttcctaa 112020 tattgccagc atcaaactca atggagtgaa agaagaagga atgaagatta aaacatgaat 112080 ttgtgtacgt ttttaagtat tttaagaata ccaaaataaa agtgtcatat gaatttctta 112140 gtatgtttct gatatagaca ggatagagtt tagtaattag caatttcttc taattttttt 112200 taaaaaaagt ttattgttgt tacttgctac aagaaattat gggacaaatt ggataaccac 112260 atgtgctggc atttgtccag gacagcccat atcaaaaggg attggggtcc atgatactgt 112320 aacagtatca tttctaatta taacttcaag gaaattcctc tctcaaagag gtagctaaga 112380 aacttattct tgtcttacaa aagaataggg tttttaggat ttaaaaacag gttgatgtgc 112440 catttttcct ccaacttatg tattttagat tctattttga ttttcactga tccatggtat 112500 ttcgttatat aatgtacccc acagtttatt gattcattct ccgattggtg gatatttatt 112560 acaaacaatg ttaaaagaac atttttctcc atgtcttcct gtaatatatt gttggacaat 112620 cactctattg ttggacaatt acttgcaact ctagaaactg tcaaagtgtt ctccaaagta 112680 gctgtaccaa attacatttc taggcgtagt aaatgagagc ttctattttt ccatgtcatc 112740 accagcacta taatacagat gctgtcatta ttctgtttta atttgtattt ctgattacca 112800 gtgatattga acatctttct gtttctttga agtacctgtt tatcaatgtt tttccatata 112860 atttttgctt tttaaatttt cttaagaaat ccttcccaac cttggaggtc ttaaagtaca 112920 ttctccttta atttttttcc aagtgtatta aggccttgct tttcttaata tgaatcttta 112980 atgtccagaa tttaattttg tgtatggtgt gagggggaga tctagttttt attttatttt 113040 tcttaagggt agtcagtttt tcccacactg cttactgaat cgcttgtctt tcccactgtt 113100 tttaatgcca cctctcttat gtattcaaga tctgtatatg tgtgggtctc tttctggact 113160 ttctactttg ttcctttggc ctatttgatt atctcagtgc taatctcaca tgttttatgc 113220 atttttataa taaatcttaa tatctgcttg agtagtccct ccacctttta tttcaaaata 113280 gtcttaatta gtcttaggct tttgcttttc cacatgaatt ttaggtttgg cttgctgttg 113340 ttccacaaag aacccagtgg ggtcttgagt aaaattgcat tgtatttaga gattaatttg 113400 gagaaaaatt attttcttgg gagtattgag actttcccgt tcatgaacat agttcatctt 113460 tcctttagtc aggtgtactc tgatgtcctt caataaagtc atacaatttt ctccacagag 113520 gtattgtaca tcatttgtta ctaatttatt ctagctatta tatagagttg gtttttataa 113580 tgcaaacctt ttctgtagtt aatatccatg tggctggata tttttatatt gcatttttat 113640 ttaacaaatc tactaaatgc ccttattatt tgaaatggct tttctgtaat ttatcttcaa 113700 ccttctgtgt agacattcat agtctgaaaa taaatacaga tttatctttt gcttttctgg 113760 attccatttc tgatcttatt ttgttggtta gacaatattg acttggtgtg ataacaggta 113820 ctcttgtctt atttcagtct tttataggaa tcattctaaa gtcaaatgac ttgatatgaa 113880 aagtgttgtc tattttagta gtcttctttt tagtagaaaa aagagaagaa gctattgatc 113940 ttggagagag atccaacagc tattttttct ttgcctttta tttcaacaaa ttattctctt 114000 atcttttgtt attttattgt tctggttcta gcttcttcag ttgacgattt tattcatcta 114060 attttcagcc atacattttc attgttcttt tgttttgttt tgttttgttt ctcatttgat 114120 gaaagcattt agtattagaa agttgcctct tggcacagcc atagttgtat ttgtggaagt 114180 tttgatattg gagacagaca ttcaaggctg ctgtgggttt atgcaagtca ctgtacagaa 114240 ctctaggggg caccactcac actatagtat atatcaatgc atccctaaga gttgtgtggt 114300 acacaacacc agtagccctg tctggtagcc ctacgtccag tgctaaatat tttgtcatct 114360 cgattgtaat cgagatttat ttcacaatgg gttttaaaat ttccaaacaa atggaggttt 114420 tgattatctt tttatttttg gattataaga tgatttcact atgaggttat gcatattact 114480 gaaactttct tttgatgtga tatttagtta attttaataa atatggcata tatgacacag 114540 tctcaatttt agatgtcagt atttatttct ttatatcatt attgataaat ttgttatatc 114600 ttctgtgtag attatttctt ttattattat cgtgtgcttc ttattttctt tctttctttt 114660 ctttttatag agacaaggtc tcactatgtt gcccaggctg gtctcaaact cctgagctca 114720 agtgatcctc tcgcctcagc ctcccaaagt gctgggatca caggcgagca ccaccacacc 114780 tcgccactta ttttctttta atgttttgat cttttaaatc tgctttgtct gatattaaga 114840 atgttttatc agctttttaa aattaagatt gacatctttt ttcccattct ccttgttttc 114900 tcctgttcag ttgatttagt ggagtttctt gtgtttctgt gatttaggtg gttttcctgt 114960 aagcagcaga tgtctatatt ttatttggct tttctttaat ctagcctaca atccctttaa 115020 acttttaaat ttgagatcat tttaaatcta caggaagttg gatgttaaga tacatatagg 115080 ggagtcccaa gtacccttca tccaatttct ccaatggcaa catctcacat aactatcctc 115140 aatctaaaaa tcagaaaggc agggcgcagt ggctaacgcc tataatccca gcactttggg 115200 aggccaaggt gcatggatca cctgaggtca ggagtttgag accagcctga ccaacatgca 115260 gaaacccagt ctttactaaa aatacaaaaa ttagccgggc atggtggcac atgcctataa 115320 tcccagctac ttggaaggct gaggcaggag aattgcttga acctgggagg tggaggttgc 115380 agtgagctga ggtcatgcca ttgcactcca gcctgggcaa caagagataa ctccatctct 115440 aaacaaacaa acaaacaaac aaaaccagga aaatggcatt ggtatagtct gtagacttta 115500 ccaattattc agtttgcata tttcaccagt ttaaatgcac tcgtttgtgt gtttgtatgt 115560 gttggggggt gggttctggc aatgttatca catgtaggtt catgttacta ccaacataat 115620 catgatacag aactttttca tcaccacaag tttcctttgc gctagccctt ttatagcacc 115680 cacccctccc tccattctta acacctgaca atcactaatc tcttctccat ctctgtaatt 115740 ttgatatttc aagaatgtta tataagtata tagtatgtaa ccttttggaa ttggcatctt 115800 tcactcagca atattcccct aagattcatc cataagtgta tcaatagttt gttcattttt 115860 atgattgtgt agtgttcttt ggtatggata taccacagtt tgcttaaccc ttcacttatt 115920 gaaagacatt tgagttgtat acattcagtt ttggggtact acaaataagc tgctatgaat 115980 atcatgtatg ggtttttatg taaatataag ttttcatttc tcttggataa atgcccaaga 116040 atgcacttgt tgggtcatat gggaaacata ggtctataat ctatttttta agaggtgagt 116100 ttgatctatt tactaataaa ccatcctagt ttttgtatgt aggaaatgtt ttaaatttgg 116160 ccacttcttg gaagatagtt taggtgaata taaaacttga agttgacaat atagtctctt 116220 aacacttggg aagtcttttg gaagtctact gtcttttctt tttgataatt tttaaggttt 116280 ttctttattg ccagtgtctt atatactttt actacaaggt gtctgagtat accggaagtg 116340 cacatccaat tagagggcac tgaagaattc tgctattctc ttttcatatg tcacttctat 116400 gcaaatccct ctgctaactc ctatcaggca tatgttggag cctcacagtc tactgtgtct 116460 tctagttttt aagctttttt ccccctttta tctcactgtg ctgctttttg cataattccc 116520 tcttcaacta tatccagtct agcacatata ccatcaactt agtgttttga ataattgttt 116580 tttgttttaa agacttcttt tttttttttt tttttttttt ttttttaaga tggagccttg 116640 ctctgttgcc caggctagag tgcagtgaca cgatctcagc tcactgcgac ctctgcctcc 116700 cgggttcaag tgattctcct gcctcagcct cctgagtagc tgatattaca ggtgcctgcc 116760 accacgcccg gctaattttt gtatttttat agagatgggg tttcccatct tggccaggtt 116820 ggtctcgaac tcctgacctc gtgatctacc cgcctcggcc tcccaaagtg ctgggattat 116880 aggcgtgagc cactgcgccc agcctaaaga cttctttttt ttaaaaaaaa attattatta 116940 tcattattat ctttagagac agggtctcac tctgtcaccc agcctagaat gctatggcat 117000 gatcatggct cactgcagcc tcaaacttct gggctcaagc aatcctccca cttctgcctc 117060 ccacatagct gggactgcaa gtgcatgcca ccatgtctgt cttgctttaa agatttctaa 117120 tagacctgtt ttcccattaa tgtttaaatt tggcttctat tgtttcatta cgtatctttt 117180 aaattttttc attttttcct ttttaattaa tcaatttatt tattaagatt tttttcttct 117240 tgccttgtct tatggcactg atatctttct ttttagatga ataatatctc tatttctctc 117300 ttaaacacct caagcaaact gattttgagg tttttgtcag attcttccat agaaataatt 117360 tcttctggag tgagttgatg ttttattttt gctgactttt tccttagcaa tatatatctt 117420 gctgtatatg ctgtatgtaa aaagtgtgtg tgtatgtgtg tgtgtgtgtg gtttttcaca 117480 ttattagttg cagacttact ttgagtaaga cttttggtgg ctgctcttgt ttccgtctct 117540 ttctcctgtc ttgtgttttc tttgctacac acactgtgct cactcctctg catttagcat 117600 ttctgtatta gcttctgtct gactctatga gatcctgagt ccagaggcaa gtcctatatg 117660 gtgtttaggc ttctgcactg tggtcatact gaagatactt tagatccagt cacagaggca 117720 gtgggggccc tgctttaact cccagtccgg ggatatattt ttgccctgct accttgccta 117780 gttccacagc ttaccaaatc tatagcttgg gcagtaaatt aggattagtt ttgttttttt 117840 tttccccctt ctttcattcc ttctaatagc ctccttttac aaaaggagtg gaagtttgga 117900 actcctgccc cagccctgcg ccatgcttta ctttaagcaa gacctagctc tggttgccac 117960 atgcatggtt gccacacttt aggccccaac acccttcaga agctggactc cagctactgt 118020 tcactggact ccagctattg ttcataattt tttttttttt tttttttttg agatggagtc 118080 tcactctgtt gcccaggctg gagtgcagtg gtgcgatctc ggctcctgca acctccgcct 118140 cccgagttca agcgattctc ctgtctcagc ctcccgagta gctgggatta caggcgcgcg 118200 ccaccaggcc cagctaattt ttttattttt agtagagaca gttttcacca tgttggtcag 118260 gctggtctca aactcctgac ctcatgttcc acccaccttg gcctcccaaa gtgctgggat 118320 tacaggcatg agccaccatg cccggctact gttcaccgtt taaatcctgg ccactgctct 118380 gcatttctgc tctgtttgtg acagagatgt tgacattgtt tgagcctagc tatgtccttt 118440 tctctccctt tgtatttttc tgtcattgat atgtttgtaa caggaagagt gcaccaaaat 118500 gagaattcac cacaatattt tgacaagaag cacagcataa ctcttctgtt tccaaagagc 118560 ctgaaatgtt tgaatcctcc catcaccacc aaccaccacc gccaccatca tcccagcact 118620 gtttctctct ctctctctct ctcacacaca cacacacaca cacacacaca cacacacaca 118680 gaacaacact caaggccagg atctcctaaa gccttgtgcc gtgggtctcc ggtctgcctt 118740 tccaagtttg tgtctcacca ttctccttgc ccatgtcagc acactgttgc ccaacaaact 118800 gagcaatttg atcttcctgg agcctattct atatcttact actttggggc tagtttgtgt 118860 tctgcctctc ttcttgaaat gccattcaaa acaaccccca gtctttcaag ctcagacaaa 118920 ctcttcctct atggaaagac ctatcaaatc tgccatttgg gaaagaattt ccctcttcta 118980 ttaacccatt acattgtttc caatttttat tacatttgcc atgatcaaaa taccatttta 119040 aaacatctta cccagtctca aacacttaac atagtcttat actgaagatg ttaactgttt 119100 attaagaaac tcttgtgtac tagatgctgt ccaaggcctt tttagataca tcgttatctc 119160 atttaattcc ttcaccaatt acggtatgag gtgaaatttg ctcattttac agataaggaa 119220 attgagcgtg agtaagtctt acccaggtcc ttatgaaact agcagattcc taagacctct 119280 ctgagaccta ctaaatagga attgctaagg atggggccca ggaatctgca ttttaaccac 119340 ctctttatat gatgctctag cactcctact gtttaaacct cgttgctcat cagaatcatc 119400 tgggggttga gggaggtggc ttaaaaatat tcagaactgg gcgggcgcag tggctcacac 119460 ctgtaatccc agcactttgg gaggctgagg caggcggatc acaaggtcag gagttcaaga 119520 ccagcctgac caatatggtg aaaccccatc tctactaaaa atacaaaaat tagccaggcg 119580 tggtgtcacg tgtctgtagt cccagctact caggaggctg aggcaggaga atcgcctgaa 119640 cccgggaggc ggaggttgca gtgagctgag actgagacac tgcactccag cctaggtgac 119700 agagcaggac tgtctcaaaa aaaaattttt tttagaacta ccaaattgga atttccagag 119760 taatggcaat ttttttttta ccagtttctc agatgagtat gaagcaggtg gttcaccaat 119820 tcctgtgtga aatataccta ggcaaatgtc agaaactggt aggccattga tagaatttgt 119880 gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtgttataaa ggtgactcaa 119940 catttaaaat caagagaatc cacataaaat atgaattcca gtttctttct aaaaaattag 120000 aaggtcgggt tacactaggt tcttatgttg caggtttgtt tgattatttt ttaaaggcag 120060 ggtcttgctc tgttgtccag gctggagtgc agtggcaatg gccatagctc actgcagcct 120120 tgaacccctg agctcaggca atcagcctca gcctcctgag tagctgggac tacaggtgca 120180 tgccaccaca cctataggct atcatgttgc aggtttctag gtgccttgat actttgatgt 120240 ccctaataat gaaagtaact gcaagaaggg cagtcagttt atgcctgaac ataaggaaaa 120300 attcatatat taggagaaca ctgtacacag atataagtac accagataaa tgaatataag 120360 ctttactaaa gattcattac caaatacaat tttactcttc aaaaatttta cttatcaaaa 120420 atttattgaa gatacctcat aatctcttcc ctttaataaa aattaaaatg taaatgaaat 120480 aaaattatag gattcctaaa tattaaagac tactaagtac aagaaacaag attagtaaat 120540 attaacaagg ttactaaata tcaaccatga gattcttgag tttctaattt gccattcact 120600 tgcagaagtt cacctgtgag ttttgcattg gtagataaag aaattcatct acctgctaca 120660 attggcctca gattctaggt gaatctgatc tgtctacagc actccaaata taaagaagaa 120720 ataatgatag tttcactttc tgtaacccta ctcagtggat tctgttgctc tacttgttta 120780 gctgtaacta ctgtcagaaa ttttctgtgg aggccaacac aggatagtcg gttttttaat 120840 gtgatacagt tgtgattgta acaggctgta taaatagcca tcagtgggta ccatggaaac 120900 cacctggaat tctttatctc tgtcctagaa agtactggag cttttgtaca gcaactgaag 120960 acatatttaa gatctttcca agtaataaaa aaggtctttg tgcattttaa acattaaata 121020 aaattaaatc acaaataatt attaaatagc aaattactag gttaggccct ttctctagct 121080 ctctgggaat catggttttc agacctatgg ttctcaaact ggggctggaa gtcaaaatta 121140 atgaacaaat taccccaaat attcttagta ctttcaaaaa tttatttgga aattacacat 121200 ttgtctgcta taaagttgca aaggctaaat aagtttttac tgattaaaaa tttacataat 121260 aatttactta tcaaaaaatt acataatatg actcatattc ccttgtaagg atacataagg 121320 atagagaacg gaaaatgtat ccttatgtat gtatccttat ccttgtatcc tttttttttt 121380 ttctggttcc actttgtttt tattcactga aaccaataaa agagttgaac acagcaaaac 121440 ttggaacaac aaggaattaa ctgggtggca gcaaagggca ccaaaagaaa agataaattg 121500 cccaaaataa ataagggctg gtgaggaaaa taaaaaatgt ttccgaaaaa agtgggctgt 121560 gatgcaaggt actgtgagat aaagaagcaa ttgtttcacg caaaaaatag aggggggcac 121620 ctcgctgaag ccagcgaggc cgctgcacca cgtggtgtca ggagacctta gcaatggccc 121680 aggttcgctg gctgcatctg ctgtgccagg cgcctactgt gcgctcctct cctcatccag 121740 caaagctcgg cctacatgga ggtttgctga ctcccccagg ccaccttagt tcctctcgga 121800 gtctgtatgg gtctgggcga gatgcaggca gcttatctgt ttatggggct gcctcctcca 121860 gtacacggag agctctttga ggcaagggac aatttgatct gtttcttcat ccttaaaatt 121920 tctgctgctt ttgctgtttc tgtgatttcc ttggtttctc cattggtgtg cttaaagcga 121980 tctcctctac acgaacgcta gggcagagca cattttcgca caggcagcgc cgcagcttgc 122040 cctggatctt gtcgattgag ttgaagtcgg acacgtggaa gacatgggtg gacttgggct 122100 ccgaggcgat ctcctccagc tcctccctga gcgcctctcc cacgtccacg gtgaagacgc 122160 ggatgccggc gcgaatgccg gcacggatgc cggcacggtg ggcagccgcc gtggcgtcca 122220 gcaccaggtc ctggctgcag ccattggtga gcagtatggc cacctgcttg taggcgcagt 122280 ccccggagcg gtggccggcg cgcggggaga agctgcgggc tgtgatgtgg tgcagcgctt 122340 cgccggtgtt ggtgttgccc tgtggtaggc gatgcatcgg gcggccgcct tgacctcctc 122400 ccgcgagccg aaaacgccca gttcgaaggc cacgttgggc aggtcgctgg agcgcacggt 122460 ccccatgcag tcggggcccg cctcgaaggt atccaccagg ttgactaccc actgctgcac 122520 cttctcaaag tcctccttgc ccacgctgga ggaggtgtcc aagaggaaga ccagattgta 122580 gtggacgctt ctgcaacctg tccgttgggc ctatcagccg ccgccccgac tccacagcgg 122640 cagcatccaa aggaagccgg ccacagcatt ccctcggagg gcagccatgg ctctcctgtt 122700 cttggggaca ggcttttctt ggccatttag gccaagaaag acgcagttag ggcctactgc 122760 agcatggcct agcagggagg cactcgggct gccagcagga gtccaatcct gggcccaggc 122820 ccactggaag cagcagctgg gagaagacac cagccccagg cagccccctc ctgggggtca 122880 cctgccagca actcgcccac tctcccccca ataatctcac aaactcagac tctagacaag 122940 acttgcagta agtctggagg ctttccccag gccagggggc cagagaggat acatacataa 123000 ggatatgtag gggaaaatta gtcaaaaata aagaagttaa gtgaagcgca aatttgaggg 123060 aaaaaaactt ttaaataaaa atctccctgg taaacttcaa attcactaaa atcatttcta 123120 tgtggatgat tttctctttt ctttaatata ttttagtagc taaataatct acacaaatga 123180 gatttaaaaa ttgaactcca gacaaatgga aacgtgaagg atcctatgag catttcctgt 123240 ccttataagg gtggaggttt tttcttcttc atctttttgt ctccaactcc tagcccagtc 123300 tttggcatgc ggtacttttt tttttttttt tttttccttt gaaaccaagt ctcgctctgt 123360 caccacgctg gagtgcagtg gcacaatctc aacttaaaac aaccaacaac tcttgggttc 123420 aaacaattct cctgcctcga cctcccgagt agctgggatt acaggcacct gccaccatgc 123480 ccaactaatt tttgtatttt tagtagagac agggtttcac tatgttggcc agactggtct 123540 caaactcctg acctcaggtg atccatctgc ctcggccccc caaaggctgg gattacaggc 123600 atgagccacc tcacccggcc acacgcagta cacttttaga cagagtctac tttgcacttc 123660 ttggtgctgt ttactggcac acatattcaa aagagtgacc atggctgatg agtgtgggtc 123720 gcaataactg atgcgtggcc aaaggtgttt cccacaacag ttggctttga ttcaccgtgt 123780 atcttctgca ctggctaccg tgtagttatg ccttgccctt catgggtcct gggattactt 123840 gactgctgcc gaggctaaca gcctcttttt tattctgatt gtgacccatt atattagtct 123900 gttggccact gactcactag tacttggaag caacccacag ctatgttgtc acatccacgt 123960 attcccctca acacgcagca aattggggtg agaccaagga aaggcccatg cacaaaggaa 124020 cctgacagct gtcagcagta gcacctgagg ccaattgtag gcggtaatag cacacactca 124080 gaaaaccata cgccagcagt gtgtgtgcat cacaatgccg ggagtgcaca tattgtgggc 124140 tcctcatcaa cagggaactc atcctgcatt gcttttatat cccaactgta cttagcacaa 124200 gactaaccat acagtaggta tctgtgccta taatgatttc accaatattt ctacatatga 124260 actactattc atcatttagg gtctcactaa atgttgcttc tttgaagata tttgcttgaa 124320 tcccctatgg cattttgtag ttacctccat gcagtaatga taatatccaa gtcattcgtt 124380 ccagagttta tatcacttat gtaaagcgta taactccaaa gctttgcaat aggtgttcaa 124440 gcagcatata atggatggat ggatggatgg atggatggtt ggttggatgg ataaacatta 124500 attgcttaga agccaagtgg agcaatttga aggagcactc tctcctatac ttcttgtttt 124560 gttatgtcaa ttcatgaaat ccccagaatg acacataaaa ggaaaccaaa atcaaattaa 124620 aacttatgaa cctaaaccat cttgtgtcat ccttggtaga catttagtgg aggaaatatg 124680 aaattgtact attcattcaa ggagttaata ggtaaaccag tttatccatc actaacttgt 124740 ttttatagca tcaacatggt gtaaagacaa aaacaatctt gaactctagt aactatcatc 124800 tatatttaat gcctctatgc tacaacagta agactctgga tgattatcag taccacttag 124860 aattagagct tcttgttaaa taattcatac atttgatggg gaagagcttc aaacaatgct 124920 caaagctcca gtaattaatg ggctaattac gagatgcttg taaaatggct taaacactga 124980 aagttcagtg taggtataat tgttttagag ttaaccctgt gtatttaaat gtcaaaaaaa 125040 atattcagtg aagatgagta gagggttggg agagagaaga gagatcataa gatatcacac 125100 cagtttagaa gtcttcacta ttgatttaag atttctaaaa aggctctgga aaggcagaat 125160 gcaggccttc ctaatgcccc aggcattttc caaccatgtc tctaatcaca taagaagaac 125220 atcacccatg agtcatagga ctctgggtac tcttagaggt cagaaaccgc tgcagtgcaa 125280 gtcctttcag cctaatcgcc tcttcactag caacgcccag gttccacaag agtgctctgt 125340 ttcattccag gacccgtggg agttaagaat tgaaggtagt tgattttttg gttggttcat 125400 ttgtttgttt ttcctccctg ttgtttgctg ttctcagaaa tgacctgctc tctgagcttt 125460 cttggagtgt aaggcatttc aattctagaa aggtggggct gggaggaaaa tggtctcctt 125520 gactgcaaac catctagctg aaatgtcttt cactcatccc actggaaggg ggaaaaaaag 125580 ccttctttag aagatgaaac attgtcttgt gtcttttagc atcgttctgg gcagtcagtc 125640 tgttaggaca tattgggcga ttataggact gtctttttag agaaagccat gggtttcaag 125700 ttagcaggaa ccatctatca attcttaaga ttatgccatg atttactgtc agagcatcat 125760 gtattctgat tttctgcctc ccatgaaaca ttgtgctttc cttttctatt gatgtatcaa 125820 ctataatagt tacaagcagc tacagaaaaa tcaatagcga gctttcatta ctgtgtacat 125880 caagtaaaga gccccccgct gcaagagcac aacttgttag atgctcacca tggaaggtgt 125940 acaacactca actgtttttt tcccagactg cattagaaaa atcaactata gaaaaattat 126000 aaaatagtat catattctac atggaagcac agagacccta taaaatctct caaagggaat 126060 ggacaggagg cattatcatg tttcaaaatg agcacagcat ttccaaagtg aatataaagg 126120 tatttaatgc gattcctacg tggtttttgt ttctggtttt cttttgcatt tgtcttctta 126180 aggtcatcag gatagtggga ggaaatactg aattagtatt tactagattg actgcgtaag 126240 cagaaagtca ccactggctg aagtgcatgc tgcaatagtc atgcgctcaa cacccagcca 126300 agcaatgagg accctaagaa ctgtgtgaat acagagtaat attaccaggg tcttaatcag 126360 atccaggagt cccagacata catatgcaaa gttttattct ctttccaagc acatgttgga 126420 aaaagaaaaa gacttaggat tttaaagcaa caaatacctt tatttgcctt tgggagcaca 126480 ttagctacca attagtgcat gtaaattgag actgctgaaa aagagaatgt atgaactgat 126540 agtctgggtg ggggactctc aaggcctcag aagttctcta gcatttcagc atcaatttgg 126600 gcaacataaa gagatttcca aagcaaatcc taacaagtcc tgaatctgaa ccatgtacaa 126660 atcataaatc ccatggaatt cccaatctta acatgtgcaa tgaatgtatt cagatctata 126720 tatttaagta attagttcat tactttctga tagttatgat ctacataaag gttttccata 126780 tgttactgtt atgatccaag tccaaactcc agttattttt tatctttaga gataatatat 126840 ttagcaagaa ggcaaaaacg tgcctgataa tttttatgtt catataagaa tgttaagaaa 126900 ctacaaaaat gtgttttgaa atattacagt aacaaacagg aaacaaacta aaaccttgag 126960 taccaggtta acttccccaa aataccattt taaaatactg atgaatttga acaagtggtt 127020 tgatttttgg gcatctgttt tgttttaggg gaagggagga atatttaaat gataaaattt 127080 tcaaatatcc catttttttc atagttttcc caacttttgt ggattttttt tctatttcgt 127140 ttttctatgc acccaaaaat tatgtgagaa ttttgcattt gcctttgaca ttctaacaac 127200 agaatgaact gccattcagc tatggtcact acattgagag tttaatgctc caaaaggtat 127260 gctctgcaag gactgtgaaa agattaatta gtctttgctg gtttcatcag aggatgctga 127320 gaaactggca acaggctctc tcctgcacca cagcccaaga ggaagatcct cttttcccca 127380 gcaaaccagg tagcaatgac atctgcaagg ttagcctttc tatttgccag tgtccctgac 127440 aattaaaaca gtgaaaataa ttcatgcatt gccaatctta attacactct tgctttcgtt 127500 tattcctttt gctactttcc tggctggtgt tttgcatgtt acttatatgc agtagtactt 127560 atctaaagcc tactttagag tagttgtcct tacaagaaat ggaagtctaa gtagagtgga 127620 atagcatttg gatgattaca gattctctgt gaattcagct aacactttcc tcaaggtagc 127680 actcatgctc ctgttaaaag tacattcttt ccacatgctt ttttcacata gttaaaaaga 127740 aatccttcca tgacatactg aaccctaata ccaaataagc tggtgcttcc cctgagccac 127800 ataggagaat gttggctctg agaatgtcgc agcatccctg cactgctgtg atgtgcagtc 127860 aacagagggt acgagctctg gcagaaaacc cagaacagga tattatgcac agtaggggct 127920 ttccaaccca gctgttccaa gccctatagg gtcaaaatga tggggaaatc cagaatgaca 127980 gtaattatgc catcaacctt acggctccct gccagagagg ttgctggtta gacatctata 128040 catctagtag ctgtttaata cattttttaa aacaggtata gtgaaagaat gcattttaag 128100 caggaattga aaatgtacta agaatgagac aataatgtat gagcaagtac ttactttgtt 128160 tcttacttta ggtaagaaaa aataaaagga aggaggaaag gtatggaggg ggagatagag 128220 ggatggaggg aaaagaaaag gaaagagaag tagatagaaa atcaaacaca gatgaaagca 128280 aagacaatta tgattataat tatttcattc cctaatcatg taagatttga attttctaat 128340 taagaaaaaa gaacaaaatt agttcatatg tcaaaaagag gattctaaaa ttgcactgac 128400 ataaatgtta ttctgtgatt cagttgcatt cttaaattgg tgtgttattt atgcaaatta 128460 tggtaagaaa aataattttg gatatttttg ttttacaaat atatttttca ctttcaccac 128520 attatttcca gaagtatctt tccttccaca ggggttccct gtctgctctt gcttcctcca 128580 gctcctcaat atatgtacct ttcagggttg tttcagcagt cctgaagttg tgtgtgtgtg 128640 taagcatgat taagagtact tttgtgggag tgtgctattg ccagcctcac agatggtgtt 128700 atttcctgtg ttagacttcc tacttactga tagctgggct cacacttgac atcctctctt 128760 aactgcctct agaccaaaac atgcaaagtc ttgcagtgtg ggagggaacc tgtggctgtg 128820 cattgggttc agttgataac aataatcacc agccctgatg agtcaccaga gagcaatggg 128880 gtgatactca agtaccagag agatggtggt ggtctctggt ggccccacca ctgtccacca 128940 cttgcaagta gataaactgg tcattaaagg agctgtggag agccagatgc agtggcacat 129000 gcctgtagcc ccagctactg cagaggctga ggcaggagga acacacaagg ccaagagttt 129060 gaatctgacc tgggcaacat agtgagaccc ctatctttaa aaataaagaa ataagtaaat 129120 ttttaaaaag aaaggcatta tgagagtttc agcagaacat ttaggaaggg tcttctagag 129180 ataatgatgg acaagtcagt aagctgcttg ttcacacact aatgtccagt tcatgttgac 129240 tgctatctac ccacgtcttc tcttctggca cctgccttag tggctggaag ctctctcaga 129300 agcttaaaaa gatgctttta ttttacctac ccaacaaggt ttctacgcat tccagcctcc 129360 aaggaggggt ggttcccctt tgtgaactga gatttaggaa tatctatgtt tacaactccg 129420 ggactaagat tcaataaagc ttcaggaggg tggaagtgca gcttgtgagg gcaaaacttt 129480 agaatccagt ggacttctta aggtcatctg aacagtgaga gtaagtacta ggctcttatc 129540 ccacttccac caccaaccaa tgcagaagtg ggattaagat tgataatcct gagatagcat 129600 taaatgtttt gatacaggca tgcaatccat aataatcaca tcagataaac agttgttctg 129660 tgcacacaat ctaacattta tgcatttttt ctttaaaaaa cctttctgca tccaaatggc 129720 acattcatta agtttaaaat gaagcacaaa agatagagat aaaatgaagc aactctataa 129780 ttatataaat tataaatctt actgtaataa ttatacagta gacttggaga aagacaggcc 129840 tttcaagaat tggtttttag agatgtgtct aatgccttaa agaagtgttt gctttaaaat 129900 cttgaaaaag cctcatgtag aagtgagatg ttgtaaagtc atcattggct ttggccactg 129960 ccaggtcgac taccagtttg ctatttgtga tgtatttcac tattttggaa cttacaaagc 130020 tattcctgat ttccttctgt taatggagga ttaatgacaa tgctgaatcc acagataata 130080 ataaaaaaat tttttttttt tttggacagt ctcactctgt cacccaggct ggagtgcaat 130140 ggtgcgatct tggctcactg caacctccac cttttgggtt caagcgattc tcctgcctca 130200 gcctcccaag tagctgggat tgcaggtgcc agccaccatg cccagctaat ttttgtattt 130260 ttagtagaga cggggttccg ccatgttggc caggctggtc tcgaactcct gacctcaagt 130320 gatccacccg cttagtctcc ccaagtgctg ggattacaga ggtgagccac cgcgcctggc 130380 ccaaaaatca aattttcaac agttacttaa atccactact tcccaagatg aaagctttat 130440 taccaactga aacttagaga actatgagtg gtcgtgggct gcctctgaac ttgctgtggg 130500 tatatttact gagccaccat gggggtcatg tgaagagtct agggttttgt tttacatcct 130560 taacacttca gttttgaaaa tccctataag acagtaatag ttctataggg taaactccaa 130620 agagggcttc tgtagggggc ataggagtgg cacccacagt tgtgggaacg tcagcaaacc 130680 tgcatcctcc ctcaggggag aggtcagagc aactcagaat attatgacta ctgaaacaac 130740 tttttgactt cacgatgctg caaagcaatc cacatccagt agaaaccata cttcaagtac 130800 ccatacaacc attctggttt ttctgagacg gagtctcact ctgtcaccca ggctggagtg 130860 cagtggcgtg atctctgctc actgcaactt ctgcctcccg ggttcaagca attctcctgc 130920 ctcagcctcc caagtagctg ggattacagg tgccccccca ccacacccgg ctaatttttg 130980 tatttttagt agagagggtg tttcaccatc ttgaccaggc tggtcttgaa ctcctgacct 131040 cgtgatccac ccgcctcggc ctcccaaagt gctgggatta caggtgtgag ccaccgcacc 131100 tggcccattc tgttttttag tttcagtaca gtattcaata aattacatga gatactcaac 131160 actttattat aaaataagtt tttggttaga tgattttgtc caactgtggg ctaatgtaag 131220 tattctgagc acatttaagg caggctaggc taagctatga tgttcagaag gttaggtgta 131280 gtaaatgaat ttgtgataat attttcaact tacgatgggc ttattgagac ataaccccat 131340 cgtaagttgg agcatctata ttgccgacat cttaacagag ccgctctctg tatatgctga 131400 ctgatacatt aggcttggga taaatcatat ctgacctttc cttataatag cactgggtgg 131460 acttcaaagg tggaagagat atttcttgtt caattaagtc atcattgcag aaagatgaaa 131520 cagatgatac tttataagcc aggcactgtc ctaccttgtg gtaattccta ttaaaacaca 131580 tttaaaagat taggaaactg aaacttagag caatttacta atttcaatgt cttatggcca 131640 gtgcagtgtt cacggattta aaatcacttc aatgcaagta tcaataattc tgctaaataa 131700 tcaggagttg actataatta atctgcaaaa accaaacaat tttccccact tgaattaatg 131760 atttctgggt gtgaaaggga atggtcacca catagtctta gtttccttcc atgcaaacct 131820 tagaattgag catagcactt acgaaaccaa tatgatcaga taataagata tcttactatt 131880 atcactgtct tagcaaaatc tgtcattaca ctgaaaaaaa aataggatag cttcttttgc 131940 aaatgtttca agctccaaaa gttcttagaa taatctttct tgttattttc tctgccacat 132000 ggttacacaa atacaaaaca aattggaaat atggattttc tgtctttcat atacaaatac 132060 atatccctga gcaattgaat gaattattaa tttgttttgt ccaaaaatgg ataagtattt 132120 ggctttaatg atcttgttag gcaactagtt tcccttccct tatagttctc aactccagag 132180 accctctctt ttcatttttc aagcaaataa ttcagaatca gtgttgatcc actgcatgat 132240 ttttccccct tcatttcaac ctctgatctt actgagcaga attttaatag ctaagggaaa 132300 tgatgtaata ataagtaaca agtatatcta gctcttaaag agtagcttta atttaactct 132360 acaaactcat aaaatattgg atatttagaa tgaatgtaga tagtaacagt tctcatatgg 132420 gcataaaatt gcaagaattt tactgattgt gatgtattac ttttagcaca aatagaatgt 132480 accaagtaca ataaacttca ctaattcagg acatttcaac ttggcaacaa aaagctcaat 132540 ttatatgtac ttaaagaaat gcaattttag taacctcagt ctaatgctta attaaagtaa 132600 catgttaaca cagtggggca caattaaaaa ggagttggga gcatcagcta taatattcaa 132660 atacctagtt tttttccaat ccaattaatc tattttgtgt gtctgtctca gaaaggatag 132720 taccagacct gccaaaggtg ttggcgggag tgagataaag tagatgcaag gggtttaata 132780 aaaattcaaa gaatgacata aatataaagt attattctca gagattacaa ttcacaatta 132840 gcctgcattt tataaaatac ctctaaaaca tcttcaacat ttaaaaattg gatgttaaaa 132900 ttggtgatac attaataata ctcttcattc cttgaatttc tgattctgtt gctgacttta 132960 gatagaattt atttttcatc agttacatac tcaaaggcta aaacaggaag gcattctttt 133020 ttgagacaaa gtctcactat gtcacccagg ctggagtgca gtggcgtgat ctcagctctc 133080 tgcaacctcc acagaaaggc attctttaaa cttcttatcc aaaataaacc caaatacaat 133140 ttccgaagta gcatagagtt caagttgctg agtcttacct agtgaaccat cagccaacac 133200 tgtagaacat catggtgctg ccatatagtg tatttcttgc tgttaggaaa gcaaaattcc 133260 ctatcctatt ctgcattctg gtattgacct gaccttaata tgtttgattc tttttttttt 133320 tttcctaata gggacagggt ctctgtcacc caggctagaa tggcccgatc acagttcatt 133380 gcaacctcaa actcctgggc ttaagcaatc cccccgcctc agactcctga gaagctgcat 133440 gccaccacac ccagctattt ttttttttaa tttttaaatt ttttgtcaaa atgggatctc 133500 actatatcag actggtctcc aactcctggc ctgaagcaat cctcctgcct cagcttccca 133560 aagtgctagg attacgggtg tgagccactt actgtgtctg gccatgtatt tgattctttt 133620 aaaatcatga atacttgttc tttcaaacaa caaatatatt atagtcatat cttggtttcc 133680 aatttctgtt taaattaaca agatgagaat tgaggcccag ggaatcagag gttctccaga 133740 tgtttccctt cattcacatc taatcctacc cctccacagg aggtatgaaa ccaactcatt 133800 gcaaagatgt cacccagggc cacatcaccc agggatactg gggttgggcg agagcataac 133860 gggacagtag agacctcacc taactttgcc ttcgtgcttg agcactaagg tcaagcaaac 133920 gttttatgaa gtttcctgcc cagtcaactg ctgagtaata tacattatac caaataaact 133980 ggttattttg tagagattgt tgaatgcttt cgttcaacat tttcattttg aaaagatttt 134040 ttaaattatt tattattatt attattatta ttatttttga gacagagtct cgctctgtcc 134100 tctaggctgg agtgcaatgg tgccatctcg gctcactgca acctccacct cccaggttta 134160 agtgattctc atgccctagc cttccaagta gctggaatta caggcgcgag ccaccagcac 134220 ccggctaatt tttgtatttt tagtaaagac ggggtttcac catgttgccc aagctggtct 134280 cgaactcctg acctcaggta atcctcccgc ctcagcctcc caaagtgctg ggattagagg 134340 cataagccac catgcctggt ctgagaagat ttttttaaga gtgttctgct gctctttagt 134400 ttcatgtaaa cttattttcc ccatggcacc ctcctcactg tcatccatgt cccttttctg 134460 cgtgagctgg tatcgcttgc taccctctaa gacctagggg atagaaaaca atgggctcta 134520 gcctgccttc tgcagggagc aaagcctaga aacaggaagc tgctacaagc aatcccaact 134580 gcactgtgtc catggagtat catgaatagt ttacacgaag aggatttctt taaaatgctg 134640 aattatgaag gagtattgat tgtgtgagta gaaatatcta gaagactaca tcttttgtct 134700 tctagtctaa tgctctgaca tggagaagtg tttccagtca acggtttatt ctgaagatag 134760 caccttgtcc actaaatgca cattacattc tcaaatttac ctttttaaag attctctttg 134820 aaataatctc tccaaaagtc agtaagaaac atgtcgagca ctaccaaagc tgagaaagtg 134880 gagctgaatc gggctcttag cctcactcac acaaaataat attttaattg gctaagctaa 134940 tatttgatcc aagttcataa aagtttgaaa tcaaataatt aaatgcaaat acagtcttca 135000 tcccaaagac gataagaatg cctttaagct aatattttta acaagaactg ttccacagcg 135060 ctctcttgta aattttatca tacctgaggc agttttcctc attcgattag ctggaaagct 135120 gaatttatcc cgaggcaaac cagacatcta gtatgggcta aattcaacaa ctggagctta 135180 aatttggctt aatatatccc cacttggatc tgcctgttta attctctttc atatgataac 135240 gttggtttat tcatagtctt gacttgccac ctgaacaaac tgaacctcat atcttattct 135300 aagagaataa aactttgcaa aaaccaccaa agtttctgaa tggaaatcaa atacaaagtg 135360 atgctcaaaa actgtttcag gacgtgagta caaaaaaaaa aaaatagtga agaggttttc 135420 tctgagggag ggctgctctt tacgaatgtg gatgtttcct atgctttggg agcagatggt 135480 ctttagcagg ataaggacta agacctccaa gaccagccaa ggcagctgca attgtgtctc 135540 aagcttgaaa ttctgcatgc tacctatttt atcaaacacc gtatgtattt ggccttattg 135600 ttaaatctat tttaaataca actttatttg aggtttaggg gcaaactagg aaattgcttc 135660 atcctatatc cctttaaatt ctgtttcctg gctcagaata tcccatcgat ttccagccag 135720 aggccttatt tttctttgat tttccgtata ttttaatgta gttttcacta tcatctgata 135780 tgcagaagtt gatacaatgt acgatctgtt tcataaaccc ctttagtata gcattctgtc 135840 ctcattttta tccctaagaa ttctagaatg caaattgcaa atgtgtatac agagggaaaa 135900 tggaagtgtt ctatgcccgt gatgtggtcc ctaacacagc tcacagcccc aaaatacagg 135960 cttcctgaaa atactcagat taccacttca caacatcaaa catatcaaat ggttttcctt 136020 ctactcattg agctcaatta cttcaatttt gaatcaaatt acactttttc tagagacaca 136080 ttataggaaa agagctttgt tatatttgaa attggttagg aatttaacaa ggtgaggaac 136140 tttaaaattg cttaagagtc taatagctgg gggtattgat acatagaaag tgctcaatat 136200 atttttattg aattaatttg catatgcttt gtattcatgg gcactgaata caaattagcc 136260 aattcaataa taaatgcatt ggttgtcttt tatgtgtgtg gtgctatacc tgtgtggtgt 136320 aggaaataag aaacataagt cagaatctct gccttctgag agaatgcaat ctagcaggag 136380 aggcaaggca taaaccagta accggagaat ccagaaaagc ttgcctggga agatgcaatt 136440 gcaaatatgt ggaagatgtt ccacagacaa gcaagcaaga agactggcgt gtgaaacaaa 136500 acggattctc ttattcgaca aatgtgaact gagctcctcc tttgtccaga cattatgcta 136560 ggcctgggaa aggttataat taacaagaga gacatatccc tgtcctcata attgacagtg 136620 aaattaccat gtaataccca atgccctgca tgatgggcaa atagagtgtg ctgtagactc 136680 acagcagaga ggacttcaag gaggcttcct ggacgtaatg atatctgcgc tgaggcccag 136740 gagattggtc aaaattatcc aaataaaggt taggggaaga aagttccagg tactggccag 136800 gcacattcaa gaaactgaaa gaagttggtg ggtggggtga aataaaacgg gatagataaa 136860 caggccagat aaatgtgttt aatctttaac ccagggtagt ggggtgccat tgaatgattt 136920 taagcagagg gaactagagg acataattgg attcacattt aaagttatca ctcatgctgt 136980 tgtgaggaaa atgcatttgg aggcggggac aatattggag gaatcagtta taaggaacag 137040 aggcgagtta cggttgcagc aatggagaat aaaggacaga ttcaagacgc aattagaaag 137100 cagaggcagc aactcggtga tggctggatt ggaaaagaag aggagaggga ggagtcatga 137160 atgaatctgg gtctcaggct tgaaatccca ggtagatatt gggtaacggg atggattctt 137220 agtccaatca ttggtataag aaaagcagga gaaggagcag gtttagaaag ccagacagat 137280 tgagctacat tttagacact gagtttgaga tgtcccctgg ctatcaggta gagacatcta 137340 gtaaatagta aacagtcata tgtacagaac caaataaagt tatatgctgc agtcttccac 137400 atgggtcact gagtgagctg gtgaaagcat tgaacacact gaaataaaat gttcaacaca 137460 tggaaaagtc caaaggattt gagaaaaaca agcaggcttg gcactacaag ccaaagcacc 137520 cagccaaaaa gtcctctttg aatccatttc ccaagaaagt acaatctata atggagtttg 137580 tgcttttcac ttgctgttat aaaacaattc tacacaaaat aaaaataaag ttggccatga 137640 atttgatatg gaagaatagc agcatgtcaa aggcaaaaaa aaaaaaaaag aagaagaaag 137700 aaaagaaaaa aagaaaaatg ttggtttagg gcaagaattt aaacaaaaaa gcttattctc 137760 atatttcctg aggatctcct ctgtgctgag cactggccag gcactaggaa tacagctgca 137820 cataagacca agtctctgcc tacacggctt tcattctagc attctagtgg gggtgacggg 137880 caattttgtt tattgttttt ttttttttga gacaagatct cactctgttt cccaggctgg 137940 agtgcagtgg cactatcttg cttcactgca gccccaactt cctgggatca agtgattctc 138000 ccacctcagc ctcccaagta gctgagacta taggcgcaga ccatcacact cactaatttt 138060 tgtatttttg tagagacagg gtttctccat gttggccagg ctggtcttga actcctgggg 138120 tcaagagatc ctccagcctt ggcctgccaa agtgctggga ttacaagcgt gagccactgc 138180 acccagcttg gcagttttta aaattagaca aatgtatgca taatgtaagg tcagtcatga 138240 acaagcaata ataagaacac atcatttagg gatataagaa aacaggtgat attgtttgga 138300 tccttgtccc tgcccaaatc tcatgtcgaa ctgtaatccc caatgctgga ggtggggcct 138360 ggtaggatgt ctttggatca tggggtcatg atccaaaaca ccaggtccct cagggcctgg 138420 tgttgtcttg gtgatagtga gttcttgcca gatctggtaa tttagaaatg tgtatcacct 138480 ccctacacat actctctctc tctggctcct gccttcacca tgtgatgtgc ctgccccacc 138540 ctcacccgcc accatgattt taatcttctt gagacctccc cagaagctga gcagatgcca 138600 acaccatgct tcctgtaaag cctgcaggtt catgagccaa ttaaacctct tttctttata 138660 aattacccag tcttaggtat ttctttatag cagtgcaaga acggcctagt ggaaatacag 138720 aattctggat tatgatcacc tctggggcat caggaattcg ttcttgggag gaacacacag 138780 atagcctgaa gggctctgac catgttctgg tcttcctgat gagtggtgga ttcataggta 138840 ttcactatac tatgtttaaa aactgacata tacattacat ttaaaacatt aattatagta 138900 aaatatgcac aatgtaaaat ttaccatctt aaccactttt ccatagattt taatagactt 138960 tttttttttt ttttgagaca gagtcttgct ctgttgtcca ggcttgagtg cagtggcatg 139020 atctcagctc actgcaacct ccacctcgtg ggttcaagtg attctcctgt ctcagcctcc 139080 tgagtagctg ggattacagg tgccagccac cacacccggc taatttttgt atttttagaa 139140 gagatggagt ttctacatgt tggccaggct ggtcttaaac tcctgacctc aagtgatcca 139200 cccgccttgg cctctcaaag tgctaggatt acaggcatga gtcaccgcac ctggccaact 139260 ttatttttta gagcagtttt tttttttttt tttttttttt tttagacgga gtcttactct 139320 tgtcacccag gctggagtgc aatggcacaa tctcagctca ctgcaacctc caactcccgg 139380 attcaagtga ttctcctgcc tcagcctccc gagtagctgg gattacaggc atgcaccacc 139440 acacccagct aatttttata tttttagtag agacagggtt tcaccatgtt gaccaggctg 139500 gtctcaaact cctgacctca ggtgatctgc ccgcctcggc ctcccaaagt gctgggatta 139560 caggcgtgaa ccaccgtgcc cagccctgga gtagttttaa gttcaccaca aaattgagca 139620 aaaggtacag agactcccca cataacccct gccccgctac tgtcagcatt cccctaccag 139680 cacaagcctc ccctactgtc agcattccac actggagtga aacctttaca atgaatgccg 139740 ctacattgac acatcctcat cacccaaagt ccgctgttca cattaggtag gtagggctcg 139800 ctgttgatgt tgtacattct atggatttgg acacacgtaa tgacatgtat ccaccattac 139860 agtatcatac agagtagtgt cactgcccta gaagtcctct gtgctctgcc cagtcatccc 139920 tccttctacc aactactggc aaccacccat ctttttattg tctccatagt tttgtctttt 139980 ccagaatgtc acacagttgg aatcatacaa tatagagcct tttcaaagtg gcttctttca 140040 tttaataata cacatttacg tttcctccat gtcttttcat gggccaacag ctcgtttcat 140100 tttagtgttg tgcaatattt catggtctgg atacaccaca gtctaaccat tcacatacta 140160 aaggacattt tggttacttt caagtttggg caattatgaa taaagctgct ataaacatcc 140220 ctatgcatgt ttttgtgcag acatacattt tcttcataac catttaaacg tatacagttc 140280 agtagtgtta agttcatttg cattgttata caaccaatat ccaaaattct tatctgacaa 140340 actgaaactc tatacccatc aaacaacaac ctctgttcct cattcctgcc aaccaccatt 140400 ctattttctg tgcctaacaa attcatttga cacaggtgcc tctaggtgcc tcttaaaagt 140460 ggactcataa gcgtttcctt tttgtgactg gcttatttca cttagcataa tgtcttcagt 140520 gtgacagaga ccagagtagc ccaccattcc ctttgaacat tggtattgta ccacaaaatc 140580 aagtggtttt caaacatttt tgatccgtgg gagctttttt tctaaaccat gtatacaaaa 140640 aaagtcaaaa gtggagaaat tcttatttct tagccttggc acctgtacaa tacaattgga 140700 aggggttggg gtggggcttg tccagagaag tccccacaaa ggtgccccat aacactagac 140760 tgtactcagt ctccatcgtg agactattat ttataatagt gatttgtggc atttaagatg 140820 tgaaatttcc ttcaaaatct caaacattaa gttgtgttac atgccaattt aaatgtcaaa 140880 tgtatattat ttcattcaaa ttatctgaaa accattcatt cgcatatcat gagacccttt 140940 agaaacggaa ctacttgact aaccagcact tcccattctc caactccagc aagtgacaga 141000 aacttgcagg cattgacaca ataggggaaa aaaaactcca ggactttaaa ataatgagcc 141060 ctgcagggtt cagattcctg ctccgcccga gggaagtctc atggtagagc atacaaggac 141120 tttagagtga gacaggcctg gtcataaatt caagatcttc ttactagcat taaaatccta 141180 gatgagcttc tcaacccctt taagcctctg tttttccact gggaaaatga tattaataat 141240 aacttcccca taagattctt aagaggatta aatgagaaaa catatgttaa agacacttgt 141300 cacattaatt ggtgtttggt aaatgttatt tcctccctca ttcttactga ctttgagatc 141360 ctgggaaagc catttaatcc ctctgattct taatttcatc atacctataa caccttctag 141420 gatagaatcc tttacaattt agcttatcct gaatcccact cctaggccag ttttctacat 141480 actctcacta actcctggga tttcacccat cacccatcag ctgtacactg ataagtccca 141540 aatctatacc tccagcccaa gcctttctct tgaggtctag acctttatgt ctggccattt 141600 cctggacatc ttcacccaat attccatgtg ccccttaaat tcaacatggc catacctaga 141660 ctccttaaat attgcttctc aaatctgctg ctcctcttgg tgacagccac caccttcttc 141720 ccttaacaga cacctggaag ccatccagga ccctcactct ttctctctgt ctctcctatt 141780 ttttattaac ccaaggccag caaaccctgt tgcatcaacc atcttgatgc ctttcaagtc 141840 cctccccacc tccttggccg ccgtatttct catctgtgtt cctgcagcag gatcctggct 141900 ggtctccctc catgagcctg ctctcccctc accctcctgc acacactagt cccttctaca 141960 cacttctggc agaatgcttt ctttaaatca gaaagctgac catttccctc tttcctaaaa 142020 ccattcagtg tttctgcctt gcttttggaa caaaatccag accatctgac atgcagcact 142080 cttcacagtc ttaaacctta gggcccatct tcatcttgcc cacctattcc ttctccacaa 142140 aggctgagct gtttaacagt gtaccaaaga cctctctgtt ctttccttct ctagggtttg 142200 tatatagacc actgtctgct aggatgtgcg ttctcttcca cgcgttgctc agctcattct 142260 aactcatctt tcaaaactcc tcaggtgtca ccttccccag ggacccctct tttctcttga 142320 accctgtgtt agctgcccat cctgtaaggg cactgcttat ctgtatcaca ttaattgagc 142380 tactgtacac agagactgtg ccttttattt ccatatctcc aacacccaga ccagagctgt 142440 taagactgaa tgaataaatg aatgaatgaa tgaatgaatg tgtatacatt gtgtatacac 142500 gaaggtatga aataataaat aaagcatgtt aagaatgttt tgtaaactac aaagcaccaa 142560 tcagttgtaa gggcctgtta tttctgtgta catatatagt atatacactt tatatctact 142620 tttttttttt ttttttaaga gacagggtct cactctgttg cccaggctgg agtgcagtgg 142680 cacaattaca gcctactgta cttgaactcc tgggctcaaa tgatgctcct acttcagcct 142740 ctcaagtagc tgagactaca ggcacacacc accacatcca gccaactttt tatttttatt 142800 tttaggggga gacaagggtc ttgctgtggt gcctaggctg gtctcaaact cctgggctga 142860 agcaatcctc catttttgta gacagctcct gccaagggca gcattttctt attattaatt 142920 tgcctatgaa agcacaaaat tatacattct agttggtaaa aataactctt gggttagtgt 142980 gtgtgcatgt gtgtgtgtgt acacacctat attattctaa gggacttatg ggaatgaatt 143040 taaaatcttg agtttcagat attgctggaa actggagaca gaatctcagt ttaggtgtca 143100 gcaccaaaat tatcctgccc tcccctcccc aatccctaaa cagccctgat ttctttttaa 143160 aagtgaactt tgttcgtatg aaaagaacga acatgttctg caacttccag aagttcttac 143220 aaaattagtt atgcagatta tccatattta gccctttaaa aaataatttt gaacattagc 143280 tccttacaga aaatctattt tctttctcct tttctagagg aaagggcctt ctgagggcaa 143340 atcgtgtgac agtttataga ttgtcatctc tctaaagacc tcaaggaaaa gaagtatttt 143400 ctatgtgcaa aacggtacct cttttttcca cctttatgtc ctttaaaaga ttagataaac 143460 cagctcgcac ctgtaattaa tcccagataa ctcccagtta ctgggaccgg gagtagctga 143520 ggccagagga tcgctcaagc ccaggagttc aaggctacag tgagctacga tgtcaccact 143580 gcttttctgc ctgggtgaca gaacgagact ctgtccctat ttattaaaaa aaaatcagac 143640 aataatatta gtaattttta aaaaataaaa aatatttaaa atctttaaaa agacaaaaaa 143700 gactaaggaa ttttttccca cttttgaaaa attaacaaag ataattacct tatcagcaaa 143760 agtcaacaca ctccatgtga gcctcacagc ccccagcccc ctggctcagc agaggaccca 143820 tttctgaaaa agtgtgttga atgacaaggt ttataggctg caccattatg gcagctacca 143880 gggaggcaga gaagagtatc ttcctcttca gagagagcct gaatgttgtg tgtgactgaa 143940 aagtcagtac tataatatat tcaagaagac ctaagggttt actttccaat aaggatggaa 144000 aaaatctgag caccccactg tgagcttatc gtaatgctgc ttcatataaa aagttggtaa 144060 ttagtccctg agtgaataaa gtagaataga tgataacaga ttgatactaa gagaagcaca 144120 aaatgctctc gccagtcatc aaaatttaaa ggctatagag aaagggttgg ggatgcctct 144180 gtctgtttac atactatttc caactcagaa tttgtaatga tagggtttat taactggtgt 144240 ttttaaattg tatgaaaatg aagcttatat aaatttcaaa ggaacgcaca gagtgccaaa 144300 tgcaggagcc tttgcaatcc agcctaaaat gccacagaag aactggtgga aatttttatc 144360 tcatatccat ctcttttcct ccagctgggg gtcttttgct aaaatccaga tgtgggacaa 144420 tgctatttaa tatgagaacc aaacagcaaa tttcaaaaac atgtatttct gggaactcca 144480 gaacatgtaa tcatttgtct agattttggt ttttttaata taatttaata tcaattcact 144540 tgtatatttc tgttgttaga gactcctgct atagatgagt tcagactccc aagttgccag 144600 ctactatcca ttacttaata tggaatagga cttgattttt attggaggga cattccagag 144660 aaaatggaaa tcaggacgat ttcagtgttt acatttgggc catagctttg cattaaacat 144720 gctttccctt tccatcccca agttctgaga atttaaattt ctatttatat gggattcatg 144780 ttttaatttt catgaaaaag tatgcatttt catcaaaact aattccatga gtaccgagga 144840 aacacactta agtttctaaa ctcttcctaa aaagtaaata caagtgaacc acataaatga 144900 gtgaaaattc caggtcttct gggaggtgtt atcatttgta ttttggcact taatctcttc 144960 cattgctttt aggtccttgt gaactatctg tgaactacct caattacagt ggaaaatcca 145020 gggtctacct gtctgtcagg tccagtccgc agcatcccag ggactgattc cagtccaaat 145080 gagaacataa gcacgtttcc cttaacacaa aactgaccag tgaaaatcct catttgcaaa 145140 acatgtaaat tagaacttga ttattcagat cacaaaagga ttcatcacag gactttttga 145200 atagaaaaga ctattacatg taaagtacag tattttattt cagggagaga tccattacat 145260 atatgccaaa tttttgaaaa tcagtttcta gttagaaaaa ggaaggaaat tggcttgtga 145320 aataatttaa caggtcaaat tcacaattgt atcaatcttg gacaaatgca ccaataatgt 145380 gaagcaagga gttaccggtg tattccctgg ggatggctga actaaagcat atcccttatc 145440 cccaggagct tacggtctgc atagggaaac agacagttaa atagacagaa gccagcatca 145500 aggcaggcag cagagcaatg atcctggaat ggcatggtca gtaaatgaga ggaattcact 145560 cagaacttct tcaggatcat tgccatgtgt atagatgtag aaacaaaata gacattcggc 145620 aagtaagaat ctttgggaca attagcagca tatgttttat tatttcatga taacattcat 145680 caaaatagct taatgggata attaactcag gcatgtggat tcaattctga tcagctttag 145740 caaaaaatag tatatttagc caaaatatga gacacctata tattttcctg ccagaaggaa 145800 aattgcacat atttcccaag ttttggggga aaagggtgtc agtttggacc agtattcata 145860 gaaattaacc atcgaggctg gacgcagtag ctcacgcctg taatcccagc actttgggag 145920 gccaaggtgg gtggatcact ggaagtcagg aatttgagac caccctagtc aacatggtga 145980 aaccccatct ctactaaaaa tataaaaatt agctgggtgt ggtgacacaa gtctgtaacc 146040 ccagctactc aggtggctga ggcaggagga ttgcttgaac tcaggaggtg gaggttgcag 146100 tgagccgaga tcgcaccact gcactacagc ctggcaacag agcaagactc tgtctcaaaa 146160 taaaaaaaag aaagaagtta accattgaat gctgagctga agactctaaa ttatcattct 146220 ataatagtaa gtggataaac caaaacttat gatctagcct ttgttttatg tttgttggta 146280 gttttctttc tttttgtttt tccttaacag agcagcatag tttatcacag aatgttaaaa 146340 ctggttctca aaaaaataca attatcaaaa aaggaaagtt tcaaacaact ttctaaaaag 146400 ggtattcttc atttttctta cattttacat tcattctatg caaatttcta catcctctct 146460 attaatctct gactgttact agctttgctt gctggtgaga gtatttttca ctgtagcgta 146520 aaataatact gcatttcaaa tttttaatag tcatgtttta atcactataa tgcaaaacaa 146580 atgtagattt ttctatcatg taccaaggta ggacatattg aaggtatttc tgattgttta 146640 tattttgcaa ttttgaacca agtatgactc tggatacata gccatactta taaatatttt 146700 taagtaactt aaaatcattt ttaaaatata ttaaataaga caggtggaat atgctttact 146760 aactgtaaag tgccgcatgg gtaaaatgtc cagagcacac caatgtggtt gccaatttaa 146820 atgccaccgg aagactcaga gctccttatt gtgtagtatt tatgtttgta caactcatca 146880 atgaataatc aactatgttt gagtctgcca tctcactttg aaagagatat ggtaccaact 146940 cactacataa ctatttcagt actaattcct cactgttttt aatttgggtc agagacttgg 147000 ggatggaaag gggaagcatg tttaatgcaa agctatggcc caaatgtaaa cactgaaatc 147060 gtcctgaaca cacttcaaca gcgaatgtat gacagcccag tgtaaagcca tttagaaata 147120 acaagatgga catgtacaca tatgtaggtt aagttcaaca gtatataatg cccaaaacag 147180 tatatagtgg gtatgaatta cttgaaccga gtttagtatc tttatccttt tagtcatagt 147240 actgtgtggt tttctccata ttctctttct tatttatttt tgtccaatta gaaaataaag 147300 cagggcaggg tggctgcatc tgtttacttt ctgagcatgg gtgtatgtaa acacacacac 147360 gtatctgtct attttttcca gaggcttcta tgtacacatc atataaaagt catactgtta 147420 acataaatca accccagaag agaaattcca gcataccgtt ttcccttgcc tattgtctgt 147480 gtgtgtgttt gtatgtcagt ctgtcttttt ttattctggc tttctctctt attcagtatt 147540 tataaggacc tttagggcag atgtctaaaa acaactgcat agtcatcagg agttaggcgg 147600 aatgaaatgc ctttgctcat cttctctaca tgagtgacca gaagaaaaaa aagaaacaca 147660 gagtatcaga ctttagaaac tacatgcagg ttaaagggca ctgaccatcc tggcttgtgt 147720 tctgcctaaa ggacaaggct ctcatttgat aaagatcatt agtcaccaag atatatattt 147780 tagagagttc ccagtagcga atattctgtt ggcagtcact ggagtgtacc agatggttca 147840 ttagcatagg ctagacaagt caaagacttt cagaatcatt tagaaaatgt caaacagaaa 147900 caagaatcct gtcacttttt attagaatta actacatcat accctggaca cagatttcac 147960 cttgggtcag aaaaattaat acagaattat atgaattgtg taatatactg ggttaagata 148020 ggtctttctc cagggactca tttgctggca atatattaag atccctctac tttaggaatc 148080 ctcaatcctt tccttttgta agatatgaaa agagttgacc ttgctcaaaa tccactggtg 148140 tctaattgat ttgaggtata tgcagaattt caacaagaca ttcttctaaa gctcttttgt 148200 gatccttttc ccaggaagtt tggtgagtgg ggtttactga atattcagca gcatgtaaag 148260 tatgtttatg tcaaaaggaa aatacatcca ttaattgaac acattgcttt agtaaacagg 148320 aattgaaatg ctattgaaat gttgcttttt tttttttttt ttttaatgca gatgtcaaaa 148380 accttgaaaa cttccagctg gtagaaggtg tccaggaaca agtcaatgcc gccctgctgg 148440 actacacaat gtgtaactac ccgcagcaga cagagaaatt tggacagcta cttcttcgac 148500 tacccgaaat ccgggccatc agtatgcagg ctgaagaata cctctactac aagcacctga 148560 acggggatgt gccctataat aaccttctca ttgaaatgtt gcatgccaaa agagcataag 148620 ttacaacccc taggagctct gctttcaaaa caaaaagaga ttgggggagt ggggaggggg 148680 aagaagaaca ggaagaaaaa aagtactctg aactgctcca agtaacgcta attaaaaact 148740 tgctttaaag atattgaatt taaaaaggca taataatcaa atacttaata gcaaataaat 148800 gatgtatcag ggtatttgta ttgcaaactg tgaatcaaag gcttcacagc cccagaggat 148860 tccatataaa agacattgta atggagtgga ttgaactcac agatggatac caacacggtc 148920 agaagaaaaa cggacagaac ggttcttgta tatttaaact gatctccact atgaagaaat 148980 ttaggaacta atcttattaa ttaggcttat acagcggggg atttgagctt acaggattcc 149040 tccatggtaa agctgaactg aaacaattct caagaatgca tcagctgtac ctacaatagc 149100 ccctccctct tcctttgaag gccccagcac ctctgccctg tggtcaccga atctgtacta 149160 aggacctgtg ttcagccaca cccagtggta gctccaccaa atcatgaaca gcctaatttt 149220 gagtgtctgt gtcttagacc tgcaaacagc taataggaaa ttctattaat atgttagctt 149280 gccattttaa atatgttctg agggttgttt tgtctcgtgt tcatgatgtt aagaaaatgc 149340 aggcagtatc cctcatctta tgtaagtgtt aattaatatt aagggaaatg actacaaact 149400 ttcaaagcaa atgctccata gctaaagcaa cttagacctt atttctgcta ctgttgctga 149460 aatgtggctt tggcattgtt ggatttcata aaaaatttct ggcaggaagt cttgttagta 149520 tacatcagtc tttttcatca tccaagtttg tagttcattt aaaaatacaa cattaaacac 149580 attttgctag gatgtcaaat agtcacagtt ctaagtagtt ggaaacaaaa ttgacgcatg 149640 ttaatctatg caaagagaaa ggaaaggatg aggtgatgta ttgactcaag gttcattctt 149700 gctgcaattg aacatcctca agagttggga tggaaatggt gatttttaca tgtgtcctgg 149760 aaagatatta aagtaattca aatcttcccc aaaggggaaa ggaagagagt gatactgacc 149820 tttttaagtc atagaccaaa gtctgctgta gaacaaatat gggaggacaa agaatcgcaa 149880 attcttcaaa tgactattat cagtattatt aacatgcgat gccacaggta tgaaagtctt 149940 gccttatttc acaattttaa aaggtagctg tgcagatgtg gatcaacatt tgtttaaaat 150000 aaagtattaa tactttaaag tcaaataaga tatagtgttt acattcttta ggtcctgagg 150060 ggcaggggga tctgtgatat aacaaaatag caaaagcggt aatttcctta atgttatttt 150120 tctgattggt aattattttt aacagtactt aattattcta tgtcgtgaga cactaaaatc 150180 aaaaacggga atctcattta gactttaatt tttttgagat tatcggcggc acaatcactt 150240 tgtagaaact gtaaaaaata aaagtatctc ctagtccctt aattttttca taaatatttc 150300 tggcttttga gtagtgtatt tatattgtat atcatacttt caactgtaga caattatgat 150360 gctaatttat tgtttcttgg tttcaccttt gtataagata tagccaagac tgaagaaacc 150420 aaatatatgt gtttactgta gcatgtcttc aaattagtgg aacttagttc agggacatag 150480 aagagtctta atgaattaaa atcattcact tgattaaatg tctgtaaatc ttcatcattc 150540 ctactgtagt ttatttaata tctattgtaa attatgtgac ttgtagcttc ctctggtttt 150600 caagtaaact caacaaggtg gagtcttacc tggttttcct ttccaagcat tgtaaattgt 150660 ataccaaaga tattagttat tacttctgtg tgtacaaaga ggattatttt attatgttta 150720 ttaatcacct ctaatactca tccacatgaa gggtacacat taggtaagct gggcgttgac 150780 tcatgcgcag tctcagtcac ccgtgttatc ttcgtggctc aaaggacaat gcaaaatcgc 150840 cgatcagagc tcatacccaa agcattacag agaacagcag catcattgcc ctccccagct 150900 gaaaaacaag ttggctagaa gatacatgga gaggaatggt gtggtcaaca gttaatgaaa 150960 cggttctatc atgcatgtgt aatgtggatg gagacaatta taagatttga ctataactat 151020 ttggagggtc tttaacattg ccaaaaaaac aaatatgttg atttttattt tattttattt 151080 tttattttaa gaggcgggat cttgatctca catgttgccc aggctggcct tgaactcctg 151140 ggctcaagca ttcctcctgc ctcagcctcc cccatagctg ggactagggg tgcatgccag 151200 catacctggc tacgttgact cttaaaatct atgttctctt attttaaaga tacagtgctc 151260 cccactgaaa attaaaccta aaaaatgtca catattggta tgttgttaac ctggtagatt 151320 aaatcatgag aatgattaga aagacgggca acacagcggg ttacatccac actgctgatc 151380 acaccaacga caggagctga taagcaagaa agcgtcacag ccagcgtctg ttcacccaag 151440 gttgacaagt gaagtttctc taatgttgat tgttagccga tttgtaacct ggcatttact 151500 tagcaactgc cttatcaatt acaggatttg ccggtaaaag cagactcaaa tataaaggtt 151560 tttggcttaa cttggtttat tatagttgct ctatgtttgt aaacagacaa tctctaatgt 151620 ctgattattt gtatcacaga tctgcagctg ccttggactt gaatccatgc aatgtttaga 151680 gtgtgaagtc agttacttgt tgatgttttc ttactgtatc aatgaaatac atattgtcat 151740 gtcagttctt gccaggaact tctcaacaaa atggaatttt ttttttcagt atttcaataa 151800 atattgatat gcccagcctg ataattttta aaagttttta tgttgtcctc attctatcgg 151860 atactaaagc ttctaaataa gagacttgac taggagtgaa atcaaaagaa tcccacagga 151920 atagatactt ttccctttag ataacttcta gagtggttgg ctgtccttcc atggatacct 151980 gaagcattaa attcaatctg agcatcatct ctacatgtga aacaaagtat tttatatcat 152040 ttactgttat aatcaataag cagaaaaatc ttaatagcat ctcacttttt tgtagagctt 152100 atgttgtcct gataactttc ccaagtgctt tcttaattca cttggtcctc agaacagatc 152160 caggaggtat tattattctc atattaaagc cccttgcaca aaaggatttg atacactagt 152220 cagaggagta gcgggaattt gaacctaggc agtttgactc cagaatcaac actcttaaac 152280 actacaccat tctgtctcta gaccaggagg acacttcaga tttgcttcaa aaggcaaaga 152340 taggccgggc gcggtggctc acgcctgtaa tcccagcact ttgggaggcc gaggcgggca 152400 gatcacctga ggttgggagt tcaagaccag cctgaccaac atggagaaac ctcgtctcta 152460 ctaaaaatac aaaattaacc gggcatggtg gcacatgcct g 152501 <210> SEQ ID NO 5 <211> LENGTH: 21 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Primer <400> SEQUENCE: 5 tcctggttac tgggcaacaa g 21 <210> SEQ ID NO 6 <211> LENGTH: 24 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Primer <400> SEQUENCE: 6 ggagagaacg aagttttgcc acta 24 <210> SEQ ID NO 7 <211> LENGTH: 23 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Probe <400> SEQUENCE: 7 cacaagccgg agccaccctc aac 23 <210> SEQ ID NO 8 <211> LENGTH: 19 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Primer <400> SEQUENCE: 8 gaaggtgaag gtcggagtc 19 <210> SEQ ID NO 9 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Primer <400> SEQUENCE: 9 gaagatggtg atgggatttc 20 <210> SEQ ID NO 10 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: PCR Probe <400> SEQUENCE: 10 caagcttccc gttctcagcc 20 <210> SEQ ID NO 11 <211> LENGTH: 3344 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <221> NAME/KEY: CDS <222> LOCATION: (127)...(1752) <400> SEQUENCE: 11 ctttcactaa gggttactgt agtctgatgt gtccttccca aggccacgaa atttgacaag 60 ctgcactttt cttttgctca atgatttctg ctttaagcca aagaactgcc tataatttca 120 ctaaga atg tct tct aat tca gat act ggg gat tta caa gag tct tta 168 Met Ser Ser Asn Ser Asp Thr Gly Asp Leu Gln Glu Ser Leu 1 5 10 aag cac gga ctt aca cct att ggt gct ggg ctt ccg gac cga cac gga 216 Lys His Gly Leu Thr Pro Ile Gly Ala Gly Leu Pro Asp Arg His Gly 15 20 25 30 tcc ccc atc ccc gcc cgc ggt cgc ctt gtc atg ctg ccc aaa gtg gag 264 Ser Pro Ile Pro Ala Arg Gly Arg Leu Val Met Leu Pro Lys Val Glu 35 40 45 acg gaa gcc ctg gga ctg gct cga tcg cat ggg gaa cag ggc cag atg 312 Thr Glu Ala Leu Gly Leu Ala Arg Ser His Gly Glu Gln Gly Gln Met 50 55 60 ccg gaa aac atg caa gtg tct caa ttt aaa atg gtg aat tac tcc tat 360 Pro Glu Asn Met Gln Val Ser Gln Phe Lys Met Val Asn Tyr Ser Tyr 65 70 75 gat gaa gat ctg gaa gag ctt tgt ccc gtg tgt gga gat aaa gtg tct 408 Asp Glu Asp Leu Glu Glu Leu Cys Pro Val Cys Gly Asp Lys Val Ser 80 85 90 ggg tac cat tat ggg ctc ctc acc tgt gaa agc tgc aag gga ttt ttt 456 Gly Tyr His Tyr Gly Leu Leu Thr Cys Glu Ser Cys Lys Gly Phe Phe 95 100 105 110 aag cga aca gtc caa aat aat aaa agg tac aca tgt ata gaa aac cag 504 Lys Arg Thr Val Gln Asn Asn Lys Arg Tyr Thr Cys Ile Glu Asn Gln 115 120 125 aac tgc caa att gac aaa aca cag aga aag cgt tgt cct tac tgt cgt 552 Asn Cys Gln Ile Asp Lys Thr Gln Arg Lys Arg Cys Pro Tyr Cys Arg 130 135 140 ttt caa aaa tgt cta agt gtt gga atg aag cta gaa gct gta agg gcc 600 Phe Gln Lys Cys Leu Ser Val Gly Met Lys Leu Glu Ala Val Arg Ala 145 150 155 gac cga atg cgt gga gga agg aat aag ttt ggg cca atg tac aag aga 648 Asp Arg Met Arg Gly Gly Arg Asn Lys Phe Gly Pro Met Tyr Lys Arg 160 165 170 gac agg gcc ctg aag caa cag aaa aaa gcc ctc atc cga gcc aat gga 696 Asp Arg Ala Leu Lys Gln Gln Lys Lys Ala Leu Ile Arg Ala Asn Gly 175 180 185 190 ctt aag cta gaa gcc atg tct cag gtg atc caa gct atg ccc tct gac 744 Leu Lys Leu Glu Ala Met Ser Gln Val Ile Gln Ala Met Pro Ser Asp 195 200 205 ctg acc att tcc tct gca att caa aac atc cac tct gcc tcc aaa ggc 792 Leu Thr Ile Ser Ser Ala Ile Gln Asn Ile His Ser Ala Ser Lys Gly 210 215 220 cta cct ctg aac cat gct gcc ttg cct cct aca gac tat gac aga agt 840 Leu Pro Leu Asn His Ala Ala Leu Pro Pro Thr Asp Tyr Asp Arg Ser 225 230 235 ccc ttt gta aca tcc ccc att agc atg aca atg ccc cct cac ggc agc 888 Pro Phe Val Thr Ser Pro Ile Ser Met Thr Met Pro Pro His Gly Ser 240 245 250 ctg caa ggt tac caa aca tat ggc cac ttt cct agc cgg gcc atc aag 936 Leu Gln Gly Tyr Gln Thr Tyr Gly His Phe Pro Ser Arg Ala Ile Lys 255 260 265 270 tct gag tac cca gac tcc tat acc agc tca ccc gag tcc ata atg ggc 984 Ser Glu Tyr Pro Asp Ser Tyr Thr Ser Ser Pro Glu Ser Ile Met Gly 275 280 285 tat tca tat atg gat agt tac cag acg agc tct cca gca agc atc cca 1032 Tyr Ser Tyr Met Asp Ser Tyr Gln Thr Ser Ser Pro Ala Ser Ile Pro 290 295 300 cat ctg ata ctg gaa ctt ttg aag tgt gag cca gat gag cct caa gtc 1080 His Leu Ile Leu Glu Leu Leu Lys Cys Glu Pro Asp Glu Pro Gln Val 305 310 315 cag gct aaa atc atg gcc tat ttg cag caa gag cag gct aac cga agc 1128 Gln Ala Lys Ile Met Ala Tyr Leu Gln Gln Glu Gln Ala Asn Arg Ser 320 325 330 aag cac gaa aag ctg agc acc ttt ggg ctt atg tgc aaa atg gca gat 1176 Lys His Glu Lys Leu Ser Thr Phe Gly Leu Met Cys Lys Met Ala Asp 335 340 345 350 caa act ctc ttc tcc att gtc gag tgg gcc agg agt agt atc ttc ttc 1224 Gln Thr Leu Phe Ser Ile Val Glu Trp Ala Arg Ser Ser Ile Phe Phe 355 360 365 aga gaa ctt aag gtt gat gac caa atg aag ctg ctt cag aac tgc tgg 1272 Arg Glu Leu Lys Val Asp Asp Gln Met Lys Leu Leu Gln Asn Cys Trp 370 375 380 agt gag ctc tta atc ctc gac cac att tac cga caa gtg gta cat gga 1320 Ser Glu Leu Leu Ile Leu Asp His Ile Tyr Arg Gln Val Val His Gly 385 390 395 aag gaa gga tcc atc ttc ctg gtt act ggg caa caa gtg gac tat tcc 1368 Lys Glu Gly Ser Ile Phe Leu Val Thr Gly Gln Gln Val Asp Tyr Ser 400 405 410 ata ata gca tca caa gcc gga gcc acc ctc aac aac ctc atg agt cat 1416 Ile Ile Ala Ser Gln Ala Gly Ala Thr Leu Asn Asn Leu Met Ser His 415 420 425 430 gca cag gag tta gtg gca aaa ctt cgt tct ctc cag ttt gat caa cga 1464 Ala Gln Glu Leu Val Ala Lys Leu Arg Ser Leu Gln Phe Asp Gln Arg 435 440 445 gag ttc gta tgt ctg aaa ttc ttg gtg ctc ttt agt tta gat gtc aaa 1512 Glu Phe Val Cys Leu Lys Phe Leu Val Leu Phe Ser Leu Asp Val Lys 450 455 460 aac ctt gaa aac ttc cag ctg gta gaa ggt gtc cag gaa caa gtc aat 1560 Asn Leu Glu Asn Phe Gln Leu Val Glu Gly Val Gln Glu Gln Val Asn 465 470 475 gcc gcc ctg ctg gac tac aca atg tgt aac tac ccg cag cag aca gag 1608 Ala Ala Leu Leu Asp Tyr Thr Met Cys Asn Tyr Pro Gln Gln Thr Glu 480 485 490 aaa ttt gga cag cta ctt ctt cga cta ccc gaa atc cgg gcc atc agt 1656 Lys Phe Gly Gln Leu Leu Leu Arg Leu Pro Glu Ile Arg Ala Ile Ser 495 500 505 510 atg cag gct gaa gaa tac ctc tac tac aag cac ctg aac ggg gat gtg 1704 Met Gln Ala Glu Glu Tyr Leu Tyr Tyr Lys His Leu Asn Gly Asp Val 515 520 525 ccc tat aat aac ctt ctc att gaa atg ttg cat gcc aaa aga gca taa 1752 Pro Tyr Asn Asn Leu Leu Ile Glu Met Leu His Ala Lys Arg Ala 530 535 540 gttacaaccc ctaggagctc tgctttcaaa acaaaaagag attgggggag tggggagggg 1812 gaagaagaac aggaagaaaa aaagtactct gaactgctcc aagtaacgct aattaaaaac 1872 ttgctttaaa gatattgaat ttaaaaaggc ataataatca aatactaata gcaaataaat 1932 gatgtatcag ggtatttgta ttgcaaactg tgaatcaaag gttcacagcc ccagaggatt 1992 ccatataaaa gacattgtaa tggagtggat tgaactcaca gatggatacc aacacggtca 2052 gaagaaaaac ggacagaacg gttcttgtat atttaaactg atctccacta tgaagaaatt 2112 taggaactaa tcttattaat taggcttata cagcggggga tttgagctta caggattcct 2172 ccatggtaaa gctgaactga aacaattctc aagaatgcat cagctgtacc tacaatagcc 2232 cctccctctt cctttgaagg cccgagcacc tctgccctgt ggtcaccgaa tctgtactaa 2292 tggacctgtg tcagccacac ccagtggtag ctccaccaaa tcatgaacag cctaatttga 2352 gtgtctgtgt cttagacctg caaacagcta ataggaaatt ctattaatat gttagcttgc 2412 catttaaata tgttctgagg gttgttttgt ctcgtgttca tgatgttaag aaaatgcagg 2472 cagtatccct catcttatgt aagtgtgaat taatattaag ggaaatgact acaaactttc 2532 aaagcaaatg ctccatagct aaagcaactt agaccttatt tctgctactg ttgctgaaat 2592 gtggctttgg cattgttgga tttcataaaa aatttctggc aggaagtctt gttagtatac 2652 atcagtcttt ttcatcatcc aagtttgtag ttcatttaaa aatacaacat taaacacatt 2712 ttgctaggat gtcaaatagt cacagttcta agtagttgga aacaaaattg acgcatgtta 2772 atctatgcaa agagaaagga aaggatgagg tgatgtattg actcaaggtt cattcttgct 2832 gcaattgaac atcctcaaga gttgggatgg aaatggtgat ttttacatgt gtcctggaaa 2892 gatattaaag taattcaaat cttccccaaa ggggaaagga agagagtgat actgaccttt 2952 ttaagtcata gaccaaagtc tgctgtagaa caaatatggg aggacaaaga atcgcaaatt 3012 cttcaaatga ctattatcag tattattaac atgcgatgcc acaggtatga aagtcttgcc 3072 ttatttcaca attttaaaag gtagctgtgc agatgtggat caacatttgt ttaaaataaa 3132 gtattaatac tttaaagtca aataagatat agtgtttaca ttctttaggt cctgaggggc 3192 agggggatct gtgatataac aaaatagcaa aagcggtaat ttccttaatg ttatttttct 3252 gattggtaat tatttttaac agtacttaat tattctatgt cgtgagacac taaaatcaaa 3312 aacgggaatc tcatttagac tttaattttt tt 3344 <210> SEQ ID NO 12 <220> FEATURE: <400> SEQUENCE: 12 000 <210> SEQ ID NO 13 <220> FEATURE: <400> SEQUENCE: 13 000 <210> SEQ ID NO 14 <220> FEATURE: <400> SEQUENCE: 14 000 <210> SEQ ID NO 15 <211> LENGTH: 213 <212> TYPE: DNA <213> ORGANISM: Homo sapiens <220> FEATURE: <400> SEQUENCE: 15 gtctttaaag cacggactta cacctattga tcgaggaaat tgccgctctg gctgcttctc 60 ctttgccgcc acgctcagac agaggtcgct tctgactagc tgtgctgggc ttccggaccg 120 acacggatcc cccatccccg cccgcggtcg ccttgtcatg ctgcccaaag tggagacgga 180 agccctggga ctggctcgat cgcatgggga aca 213 <210> SEQ ID NO 16 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 16 tcggtccgga agcccagcac 20 <210> SEQ ID NO 17 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 17 gcttgtcaaa tttcgtggcc 20 <210> SEQ ID NO 18 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 18 ttagaagaca ttcttagtga 20 <210> SEQ ID NO 19 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 19 ttgggcagca tgacaaggcg 20 <210> SEQ ID NO 20 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 20 ccactttggg cagcatgaca 20 <210> SEQ ID NO 21 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 21 cgtctccact ttgggcagca 20 <210> SEQ ID NO 22 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 22 gcttccgtct ccactttggg 20 <210> SEQ ID NO 23 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 23 ccctgttccc catgcgatcg 20 <210> SEQ ID NO 24 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 24 tgagacactt gcatgttttc 20 <210> SEQ ID NO 25 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 25 taaattgaga cacttgcatg 20 <210> SEQ ID NO 26 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 26 cattttaaat tgagacactt 20 <210> SEQ ID NO 27 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 27 ttcaccattt taaattgaga 20 <210> SEQ ID NO 28 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 28 agtaattcac cattttaaat 20 <210> SEQ ID NO 29 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 29 ataggagtaa ttcaccattt 20 <210> SEQ ID NO 30 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 30 gatcttcatc ataggagtaa 20 <210> SEQ ID NO 31 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 31 ttccagatct tcatcatagg 20 <210> SEQ ID NO 32 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 32 agctcttcca gatcttcatc 20 <210> SEQ ID NO 33 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 33 gcccttacag cttctagctt 20 <210> SEQ ID NO 34 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 34 tgtctctctt gtacattggc 20 <210> SEQ ID NO 35 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 35 agcttaagtc cattggctcg 20 <210> SEQ ID NO 36 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 36 atcacctgag acatggcttc 20 <210> SEQ ID NO 37 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 37 cttggatcac ctgagacatg 20 <210> SEQ ID NO 38 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 38 agaggtaggc ctttggaggc 20 <210> SEQ ID NO 39 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 39 ggacttctgt catagtctgt 20 <210> SEQ ID NO 40 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 40 caaagggact tctgtcatag 20 <210> SEQ ID NO 41 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 41 ggcattgtca tgctaatggg 20 <210> SEQ ID NO 42 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 42 ttcaaaagtt ccagtatcag 20 <210> SEQ ID NO 43 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 43 cacacttcaa aagttccagt 20 <210> SEQ ID NO 44 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 44 atactactcc tggcccactc 20 <210> SEQ ID NO 45 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 45 agaagatact actcctggcc 20 <210> SEQ ID NO 46 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 46 ttcatttggt catcaacctt 20 <210> SEQ ID NO 47 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 47 gcagcttcat ttggtcatca 20 <210> SEQ ID NO 48 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 48 aatagtccac ttgttgccca 20 <210> SEQ ID NO 49 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 49 atagggcaca tccccgttca 20 <210> SEQ ID NO 50 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 50 ttattatagg gcacatcccc 20 <210> SEQ ID NO 51 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 51 gggttgtaac ttatgctctt 20 <210> SEQ ID NO 52 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 52 gttttgaaag cagagctcct 20 <210> SEQ ID NO 53 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 53 cctttgattc acagtttgca 20 <210> SEQ ID NO 54 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 54 ccattacaat gtcttttata 20 <210> SEQ ID NO 55 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 55 tcttcatagt ggagatcagt 20 <210> SEQ ID NO 56 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 56 ctaaatttct tcatagtgga 20 <210> SEQ ID NO 57 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 57 tttaccatgg aggaatcctg 20 <210> SEQ ID NO 58 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 58 ctcaaattag gctgttcatg 20 <210> SEQ ID NO 59 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 59 aatagaattt cctattagct 20 <210> SEQ ID NO 60 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 60 tcttaacatc atgaacacga 20 <210> SEQ ID NO 61 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 61 tagcagaaat aaggtctaag 20 <210> SEQ ID NO 62 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 62 aagccacatt tcagcaacag 20 <210> SEQ ID NO 63 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 63 tgccaaagcc acatttcagc 20 <210> SEQ ID NO 64 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 64 gactgatgta tactaacaag 20 <210> SEQ ID NO 65 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 65 tgcatagatt aacatgcgtc 20 <210> SEQ ID NO 66 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 66 gagtcaatac atcacctcat 20 <210> SEQ ID NO 67 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 67 acagcagact ttggtctatg 20 <210> SEQ ID NO 68 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 68 tagtcatttg aagaatttgc 20 <210> SEQ ID NO 69 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 69 gttaataata ctgataatag 20 <210> SEQ ID NO 70 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 70 tgatccacat ctgcacagct 20 <210> SEQ ID NO 71 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 71 tgtaaacact atatcttatt 20 <210> SEQ ID NO 72 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 72 ctcaggacct aaagaatgta 20 <210> SEQ ID NO 73 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 73 acattaagga aattaccgct 20 <210> SEQ ID NO 74 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 74 agtctaaatg agattcccgt 20 <210> SEQ ID NO 75 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 75 caatttcctc gatctgaggg 20 <210> SEQ ID NO 76 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 76 cgggtcttac agctagtcag 20 <210> SEQ ID NO 77 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 77 ggtggcatac cttaagttct 20 <210> SEQ ID NO 78 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 78 tctccccgtt acagcaaaag 20 <210> SEQ ID NO 79 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 79 ctacactcac ttgttgccca 20 <210> SEQ ID NO 80 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 80 ggcagaggtc ctgactgggc 20 <210> SEQ ID NO 81 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 81 caggttttgc tgtttcaaaa 20 <210> SEQ ID NO 82 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 82 gttcacaagg acctaaaagc 20 <210> SEQ ID NO 83 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 83 tttccctgga ctctgtactt 20 <210> SEQ ID NO 84 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 84 ccaccttgtt gagtttactt 20 <210> SEQ ID NO 85 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 85 gcatcataat tgtctacagt 20 <210> SEQ ID NO 86 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 86 tgaactaagt tccactaatt 20 <210> SEQ ID NO 87 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 87 ctcttctatg tccctgaact 20 <210> SEQ ID NO 88 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 88 tttcctcgat caataggtgt 20 <210> SEQ ID NO 89 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 89 cagccagagc ggcaatttcc 20 <210> SEQ ID NO 90 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: Artificial Sequence <220> FEATURE: <223> OTHER INFORMATION: Antisense Oligonucleotide <400> SEQUENCE: 90 agcccagcac agctagtcag 20 <210> SEQ ID NO 91 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 91 gtgctgggct tccggaccga 20 <210> SEQ ID NO 92 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 92 cgccttgtca tgctgcccaa 20 <210> SEQ ID NO 93 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 93 tgtcatgctg cccaaagtgg 20 <210> SEQ ID NO 94 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 94 tgctgcccaa agtggagacg 20 <210> SEQ ID NO 95 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 95 cccaaagtgg agacggaagc 20 <210> SEQ ID NO 96 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 96 cgatcgcatg gggaacaggg 20 <210> SEQ ID NO 97 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 97 gaaaacatgc aagtgtctca 20 <210> SEQ ID NO 98 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 98 catgcaagtg tctcaattta 20 <210> SEQ ID NO 99 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 99 aagtgtctca atttaaaatg 20 <210> SEQ ID NO 100 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 100 tctcaattta aaatggtgaa 20 <210> SEQ ID NO 101 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 101 aaatggtgaa ttactcctat 20 <210> SEQ ID NO 102 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 102 ttactcctat gatgaagatc 20 <210> SEQ ID NO 103 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 103 cctatgatga agatctggaa 20 <210> SEQ ID NO 104 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 104 gatgaagatc tggaagagct 20 <210> SEQ ID NO 105 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 105 aagctagaag ctgtaagggc 20 <210> SEQ ID NO 106 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 106 gccaatgtac aagagagaca 20 <210> SEQ ID NO 107 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 107 cgagccaatg gacttaagct 20 <210> SEQ ID NO 108 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 108 gaagccatgt ctcaggtgat 20 <210> SEQ ID NO 109 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 109 catgtctcag gtgatccaag 20 <210> SEQ ID NO 110 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 110 gcctccaaag gcctacctct 20 <210> SEQ ID NO 111 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 111 acagactatg acagaagtcc 20 <210> SEQ ID NO 112 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 112 ctatgacaga agtccctttg 20 <210> SEQ ID NO 113 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 113 cccattagca tgacaatgcc 20 <210> SEQ ID NO 114 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 114 ctgatactgg aacttttgaa 20 <210> SEQ ID NO 115 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 115 actggaactt ttgaagtgtg 20 <210> SEQ ID NO 116 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 116 gagtgggcca ggagtagtat 20 <210> SEQ ID NO 117 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 117 ggccaggagt agtatcttct 20 <210> SEQ ID NO 118 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 118 aaggttgatg accaaatgaa 20 <210> SEQ ID NO 119 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 119 tgatgaccaa atgaagctgc 20 <210> SEQ ID NO 120 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 120 tgggcaacaa gtggactatt 20 <210> SEQ ID NO 121 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 121 tgaacgggga tgtgccctat 20 <210> SEQ ID NO 122 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 122 ggggatgtgc cctataataa 20 <210> SEQ ID NO 123 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 123 aagagcataa gttacaaccc 20 <210> SEQ ID NO 124 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 124 aggagctctg ctttcaaaac 20 <210> SEQ ID NO 125 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 125 tgcaaactgt gaatcaaagg 20 <210> SEQ ID NO 126 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 126 tataaaagac attgtaatgg 20 <210> SEQ ID NO 127 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 127 actgatctcc actatgaaga 20 <210> SEQ ID NO 128 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 128 tccactatga agaaatttag 20 <210> SEQ ID NO 129 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 129 caggattcct ccatggtaaa 20 <210> SEQ ID NO 130 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 130 catgaacagc ctaatttgag 20 <210> SEQ ID NO 131 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 131 agctaatagg aaattctatt 20 <210> SEQ ID NO 132 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 132 tcgtgttcat gatgttaaga 20 <210> SEQ ID NO 133 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 133 cttagacctt atttctgcta 20 <210> SEQ ID NO 134 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 134 ctgttgctga aatgtggctt 20 <210> SEQ ID NO 135 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 135 gctgaaatgt ggctttggca 20 <210> SEQ ID NO 136 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 136 cttgttagta tacatcagtc 20 <210> SEQ ID NO 137 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 137 gacgcatgtt aatctatgca 20 <210> SEQ ID NO 138 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 138 atgaggtgat gtattgactc 20 <210> SEQ ID NO 139 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 139 catagaccaa agtctgctgt 20 <210> SEQ ID NO 140 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 140 gcaaattctt caaatgacta 20 <210> SEQ ID NO 141 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 141 agctgtgcag atgtggatca 20 <210> SEQ ID NO 142 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 142 aataagatat agtgtttaca 20 <210> SEQ ID NO 143 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 143 tacattcttt aggtcctgag 20 <210> SEQ ID NO 144 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 144 agcggtaatt tccttaatgt 20 <210> SEQ ID NO 145 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 145 acgggaatct catttagact 20 <210> SEQ ID NO 146 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 146 agaacttaag gtatgccacc 20 <210> SEQ ID NO 147 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 147 cttttgctgt aacggggaga 20 <210> SEQ ID NO 148 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 148 tgggcaacaa gtgagtgtag 20 <210> SEQ ID NO 149 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 149 gcccagtcag gacctctgcc 20 <210> SEQ ID NO 150 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 150 ttttgaaaca gcaaaacctg 20 <210> SEQ ID NO 151 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 151 gcttttaggt ccttgtgaac 20 <210> SEQ ID NO 152 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 152 aagtaaactc aacaaggtgg 20 <210> SEQ ID NO 153 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 153 actgtagaca attatgatgc 20 <210> SEQ ID NO 154 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 154 aattagtgga acttagttca 20 <210> SEQ ID NO 155 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 155 agttcaggga catagaagag 20 <210> SEQ ID NO 156 <211> LENGTH: 20 <212> TYPE: DNA <213> ORGANISM: H. sapiens <220> FEATURE: <400> SEQUENCE: 156 ctgactagct gtgctgggct 20 

What is claimed is:
 1. A compound 8 to 80 nucleobases in length targeted to a nucleic acid molecule encoding fetoprotein transcription factor, wherein said compound specifically hybridizes with said nucleic acid molecule encoding fetoprotein transcription factor (SEQ ID NO: 4) and inhibits the expression of fetoprotein transcription factor.
 2. The compound of claim 1 comprising 12 to 50 nucleobases in length.
 3. The compound of claim 2 comprising 15 to 30 nucleobases in length.
 4. The compound of claim 1 comprising an oligonucleotide.
 5. The compound of claim 4 comprising an antisense oligonucleotide.
 6. The compound of claim 4 comprising a DNA oligonucleotide.
 7. The compound of claim 4 comprising an RNA oligonucleotide.
 8. The compound of claim 4 comprising a chimeric oligonucleotide.
 9. The compound of claim 4 wherein at least a portion of said compound hybridizes with RNA to form an oligonucleotide-RNA duplex.
 10. The compound of claim 1 having at least 70% complementarity with a nucleic acid molecule encoding fetoprotein transcription factor (SEQ ID NO: 4) said compound specifically hybridizing to and inhibiting the expression of fetoprotein transcription factor.
 11. The compound of claim 1 having at least 80% complementarity with a nucleic acid molecule encoding fetoprotein transcription factor (SEQ ID NO: 4) said compound specifically hybridizing to and inhibiting the expression of fetoprotein transcription factor.
 12. The compound of claim 1 having at least 90% complementarity with a nucleic acid molecule encoding fetoprotein transcription factor (SEQ ID NO: 4) said compound specifically hybridizing to and inhibiting the expression of fetoprotein transcription factor.
 13. The compound of claim 1 having at least 95% complementarity with a nucleic acid molecule encoding fetoprotein transcription factor (SEQ ID NO: 4) said compound specifically hybridizing to and inhibiting the expression of fetoprotein transcription factor.
 14. The compound of claim 1 having at least one modified internucleoside linkage, sugar moiety, or nucleobase.
 15. The compound of claim 1 having at least one 2′-O-methoxyethyl sugar moiety.
 16. The compound of claim 1 having at least one phosphorothioate internucleoside linkage.
 17. The compound of claim 1 having at least one 5-methylcytosine.
 18. A method of inhibiting the expression of fetoprotein transcription factor in cells or tissues comprising contacting said cells or tissues with the compound of claim 1 so that expression of fetoprotein transcription factor is inhibited.
 19. A method of screening for a modulator of fetoprotein transcription factor, the method comprising the steps of: a. contacting a preferred target segment of a nucleic acid molecule encoding fetoprotein transcription factor with one or more candidate modulators of fetoprotein transcription factor, and b. identifying one or more modulators of fetoprotein transcription factor expression which modulate the expression of fetoprotein transcription factor.
 20. The method of claim 19 wherein the modulator of fetoprotein transcription factor expression comprises an oligonucleotide, an antisense oligonucleotide, a DNA oligonucleotide, an RNA oligonucleotide, an RNA oligonucleotide having at least a portion of said RNA oligonucleotide capable of hybridizing with RNA to form an oligonucleotide-RNA duplex, or a chimeric oligonucleotide.
 21. A diagnostic method for identifying a disease state comprising identifying the presence of fetoprotein transcription factor in a sample using at least one of the primers comprising SEQ ID NOS: 5 or 6, or the probe comprising SEQ ID NO:
 7. 22. A kit or assay device comprising the compound of claim
 1. 23. A method of treating an animal having a disease or condition associated with fetoprotein transcription factor comprising administering to said animal a therapeutically or prophylactically effective amount of the compound of claim 1 so that expression of fetoprotein transcription factor is inhibited.
 24. The method of claim 23 wherein the disease or condition is a hyperproliferative disorder. 